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Embryology - User contributions [en-gb]
2024-03-28T09:56:31Z
User contributions
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https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3332339&diff=162362
User:Z3332339
2014-11-05T12:21:42Z
<p>Z3332339: </p>
<hr />
<div>{{StudentPage2014}} <br />
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==Lab Attendance==<br />
Lab1 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 12:45, 6 August 2014 (EST)<br />
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http://www.ncbi.nlm.nih.gov/pubmed<br />
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[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
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<pubmed>25084016</pubmed><br />
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Lab2 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:12, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 27 August 2014 (EST)<br />
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Lab 5--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 3 September 2014 (EST)<br />
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Lab 6--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:12, 10 September 2014 (EST)<br />
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Lab 7--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 17 September 2014 (EST)<br />
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Lab 8--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:24, 24 September 2014 (EST)<br />
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Lab 9--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:10, 8 October 2014 (EST)<br />
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Lab 10--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 12:05, 15 October 2014 (EST)<br />
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Lab 11--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:16, 22 October 2014 (EST)<br />
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Lab 12--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:08, 29 October 2014 (EST)<br />
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== Lab Assessment 1==<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/24952156 PMID24952156]<br />
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'''A role for carbohydrate recognition in mammalian sperm-egg binding''' <br />
The primary focus of this article is on the first stage of fertilization, the binding of sperm to the specialised extracellular matrix of the egg, known as the zona pelluicda (ZP). The article suggests that the mammalian egg cell has a specialised carbohydrate site on the ZP for which the sperm recognises and binds to, enabling the fusion of genetic information between these two gametes. <br />
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The article explains how it was previously thought that data obtained from mouse sperm-egg interactions could explain human sperm-cell binding. However, recent research has suggested that the mouse model cannot be directly applied to the human model. Thus, this research paper investigates sperm-ZP interactions, using humans as the predominant model in finding the specific requirements for human sperm-egg binding which couldn’t previously be explained by the mouse model. <br />
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This article also uses a review that focused on the identification of the egg binding proteins associated with the binding of human sperm to the egg. Their findings concluded identifying the role for carbohydrate recognition on the ZP. These carbohydrates have specific sequences that cause restriction of ZP glycosylation in humans that could not otherwise be explained in mouse and pig models or are not the same for humans. This finding suggests that the regulation of glycosylation could be directly correlated with the degree of organismal complexity. Evidence favouring this concept would require the sequencing of ZP glycoproteins from other mammals at different levels of the evolutionary ladder, which could be are areas of future directions for this research.<br />
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[http://www.ncbi.nlm.nih.gov/pubmed/25044079 PMID25044079]<br />
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'''Examining the temperature of embryo culture in in vitro fertilization: a randomized controlled trial comparing traditional core temperature (37°C) to a more physiologic, cooler temperature (36°C)'''<br />
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The study undertaken in this article was to determine if better clinical outcomes of IVF resulted from embryo cultures in cooler temperatures (36 degrees) as oppose to the traditional core temperature of (37 degrees). <br />
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The method of investigation: retrieving eight or more oocytes from a female of 42 years of age, with infertile couples (n=52). These mature oocytes were divided into two groups to be cultured at different temperatures; one group at 36 degrees, the other at 37 degrees. The rate of development and expansion of blastocysts (volume), fertilization, aneuploidy and sustained implantation were the factors measured to in order to determine which of these conditions clinically improved the environment best for embryonic development. This could potentially change the temperatures of which in vitro fertilization takes places in clinics in the future. <br />
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However, the results concluded that IVF culture at 36 degrees does not improve the conditions for blastulation and pregnancy rates in human in IVF. Thus, maintaining the existing temperature or changing it to 26 degrees does not alter the effects or success of IVF.<br />
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--[[User:Z8600021|Mark Hill]] These articles are good and your descriptions are appropriate. We will discuss in later tutorials how to format the referencing correctly. [[Help:Reference_Tutorial]] (5/5)<br />
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==Lab Assessment 2==<br />
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=='''Oocytes with Dark Zona Pelluica affect fertility'''==<br />
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[[File:Oocytes with DZP demonstrate affect on fertility.png|600px]]<br />
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Human mature oocytes with a normal (A) and dark (B) zona pelluicda. Oocytes with a DZP (dark zona pelluicda) have demonstrated a lower success of fertlization and implantation in clinical pregnancy rates in IVF/ICSI cycles. Patients with normal zona pellucida (NZP) were used as the control group.<br />
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===Reference===<br />
<pubmed>24586757</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0089409 PLoS One.]<br />
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[http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0089409#pone-0089409-g002 Figure 2. Human mature oocytes with a normal (A) and dark (B) zona pellucida.Scale bar (A, B): 100 µm. doi:10.1371/journal.pone.0089409.g002]<br />
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Shi W, Xu B, Wu L-M, Jin R-T, Luan H-B, et al. (2014) Oocytes with a Dark Zona Pellucida Demonstrate Lower Fertilization, Implantation and Clinical Pregnancy Rates in IVF/ICSI Cycles. PLoS ONE 9(2): e89409. doi:10.1371/journal.pone.0089409<br />
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===Copyright===<br />
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© 2014 Shi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
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--[[User:Z8600021|Mark Hill]] This is a good image for the assessment and I have made some minor changes to the information associated with the file. You do not need to include the copyright and student template on your page, just with the image. (5/5)<br />
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{{Template:Student Image}}<br />
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==Lab Assessment 3==<br />
===2.Identify Current Research, Models and Findings===<br />
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===Physiological factors in fetal lung growth===<br />
<pubmed>3052746</pubmed><br />
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This article looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite. It is crucial to the function of the neonatal lung because:<br />
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A. Its high viscosity and low surface tension stabilize the diameter of the alveoli and prevent their collapse after each expiration. <br />
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B. Because the alveoli remain partially open, they are expanded on inspiration with much less expenditure of energy. [ANAT 2241 LEC 11-Respriation]<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential. <br />
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[this will be looked at further as the research project progresses]<br />
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===Lung morphogenesis revisited: old facts, current ideas===<br />
<pubmed>11002333</pubmed><br />
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Classical ideas -4 basic rules vs their review<br />
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===Genetic control of lung development===<br />
<pubmed>12890942</pubmed><br />
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Current concepts of lung development<br />
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===Effects of hormones on fetal lung development===<br />
<pubmed>15550344</pubmed><br />
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===The fetal respiratory system as target for antenatal therapy===<br />
<pubmed>24753844</pubmed><br />
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--[[User:Z8600021|Mark Hill] These references are more than appropriate (5/5).<br />
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==Lab Assessment 4==<br />
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===1. An example of a use of Stem Cell Cord Therapy===<br />
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<pubmed>25101638</pubmed><br />
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Human mesenchymal stem cells MSCs (human embryonic tissue) have been used on animal models such as mice for their therapeutic qualities involved in regenerating liver tissue. This paper specifically looks at the possibility of using MSC to be used to treat degenerating organs after the discovering that MSC can be used as a substitute for liver acute failure on the mouse model. The human umbilical cord MSCs (hUCMSCs) have the capability to differentiate into hepatocyte-like cells due to their multipotence, meaning the that all the functions of the typical hepatocyte such as secretion of albumin and storage of glycogen can now be carried out from the hUCMSCs. <br />
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To imitate the environment for hUCMSCs to proliferate and differentiate into functional hepatocyte-like cells (iHeps), hUCMSCs were exposed to the growth factors, cytokinesis and chemicals. The induced i-heps demonstrated similar morphology to that of human hepatocytes, however the more significant part was evaluating their hepatic functions. Demonstration of hepatocyte function of i-Heps in vitro, is summarised in their findings as they compared i-Heps to hUCMS.<br />
1) More glycogen was stored in i-Heps than in hUCMSC<br />
2) 12 times more urea was produced by i-Heps than hUCMSC <br />
3) lower levels of glycogen were stored in hUCMSC <br />
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This has had a significant clinical research relevance in treating acute liver failure and the possibility of treating other diseases as well.<br />
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===2.Vascular shunts present in the embryo but closed postnatally ===<br />
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# The Foramen ovale -located between the right and left atrium.<br />
# The Ductus arteriosus - located between the pulmonary artery and descending aorta.<br />
# The Ductus venosus - located in the liver between the umbilical vein and IVC.<br />
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==Lab Assessment 5==<br />
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'''Abnormality of Respiratory development: Asthma'''<br />
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Asthma is a disease that affects 10% of the population in Australia according to the Asthma organisation of Australia. <ref>http://www.asthmaaustralia.org.au/Statistics.aspx</ref>.This prevalence in Australia is significantly high compared to other countries. However, the cause for our high ranking amongst other countries is unknown. In this research paper, a strong association between low birth weight, short gestational age and fetal growth restriction is shown to influence the development of asthma in children.<br />
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A primary part of their research involved a cohort study on infants born between 1979-2005, and following up during different stages of their development postnatally; 3 years old, first hospitalisation for asthma, 18th birthday etc. A majority of the subjects were hospitalized for asthma during their follow up that was consistent with their 3 findings that influenced infant hospitalisation because of the disease.<br />
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One conclusion from the study was that pre-term neonates may have under developed lungs that are smaller than the fetuses who completed the full gestation period (38weeks). Incompetent lungs could be due to restricted growth factors, inhibiting full lung capacity. Fetuses that were born small yet completed the gestational period, were infants unaffected by asthma and hence hospitalisation from it. As predicted, the risk of hospitalization for childhood asthma was proportional to lower birth weights, with only 1kg making a remarkable difference. This was a similar case for shorter gestational age. <br />
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===References===<br />
<references/><br />
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<pubmed>24602245</pubmed><br />
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==Lab Assessment 7==<br />
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One of the most important developmental aspects of the male gonads is the descent of the testes. Recent research has discovered that the normal descent of the testes during male gonad development can be interrupted when exposed to paracetamol, aspirin, and Indomethacin (a nonsteroidal anti-inflammatory drug) causing cryptorchidism. Cryptorchidism is an abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males. Descent may complete post-natally in the first year, failure to descend can result in sterility <ref>https://php.med.unsw.edu.au/embryology/index.php?title=File:Cryptorchidism.jpg.</ref> . The aim of this research article was to determine whether common analgesic (pain relief drugs as mentioned above) disrupted the morphology and endocrine function of the human testis <ref><pubmed>24030937</pubmed></ref> .<br />
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Amongst the outcomes measured from comparing human fetal testes exposed to analgesic and those were not exposed to analgesic, were testosterone and the anti-Müllerian hormone. The number of testicular cells was then counted through histological and image analysis, as the testing of this occurred ''in vitro''. The conclusion from this research identified that when fetuses were exposed to analgesic from pregnancy this cause disturbances in the fetal testis. These disturbances increase when small, critical age windows, such as when male gonad development takes place.<br />
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Data from a recent study of male human fetal (between 10 and 35 weeks) gonad position <ref>http://php.med.unsw.edu.au/embryology/index.php?title=BGD_Lecture_-_Sexual_Differentiation.</ref><br />
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*10 to 23 weeks - (9.45%) had migrated from the abdomen and were situated in the inguinal canal<br />
*24 to 26 weeks - (57.9%) had migrated from the abdomen<br />
*27 to 29 weeks - (16.7%) had not descended to the scrotum<br />
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Thus, what is advised by this article is a caution concerning consumption of analgesics such as aspirin, indomethacin, and paracetamol during pregnancy that may cause an inhibition of normal fetal testes morphology and endocrine function.<br />
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===References===<br />
<references/><br />
<ref>https://php.med.unsw.edu.au/embryology/index.php?title=File:Cryptorchidism.jpg.</ref><br />
<ref>https://embryology.med.unsw.edu.au/embryology/index.php?title=BGD_Lecture_-_Sexual_Differentiation.</ref><br />
<ref>http://embryology.med.unsw.edu.au/embryology/index.php?title=ANAT2341_Lab_7.</ref><br />
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The embryonic layers and tissues that contribute to developing teeth.<br />
The stages in tooth development include:<br />
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*Lamina<br />
*Placode<br />
*Bud<br />
*Cap<br />
*Bell<br />
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The tissues that contribute to developing teeth include:<br />
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*Odontoblasts<br />
*Ameloblasts<br />
*Periodontal ligament<br />
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==Lab Assessment 8==<br />
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===Embryonic Development of the Ovary===<br />
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====Indifferent Stage====<br />
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Much of the gonad development between males and females is analogous during embryonic development. Differentiation of the gonads (testis or ovary) occur late in embryonic development. Sexual differentiation is determined early on, where double X chromosomes in embryo will trigger the female gonad development whereas, an inherent XY chromosome will determine that the sex of this embryo will be a male. More particularly, the expression of the SRY gene on the Y chromosome determines the gender of the conceptus and signals pathways for male gonad development. Thus, when the SRY gene is not expressed, the human embryo will follow the gonad development of females.<br />
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Another contributing factor to gonad development after sex determining genes is hormone production. For example, at the urogenital sinus the presence dihyrdrotestosterone (DHT) determines males development and the absence of dihyrdrotestosterone (DHT) determines female development. <br />
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====Differentiation Stage====<br />
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• In the absence of the Y chromosome, female development occurs<br />
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• somatic support cells differentiate into follicle cells (instead of sertoli cells in males)<br />
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• From the intermediate mesoderm, the development of the Müllerian duct Müllerian duct persists and is stimulated to differentiate into the uterine tube, the uterus and the upper vagina. However, mesonephric ducts degenerate. The opposite occurs for the opposite sex.<br />
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• Presence of dihyrdrotestosterone (DHT)<br />
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• Absence of Anti- Müllerian hormone (AMH), since sertoli cells are not differentiated by SRY gene<br />
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• Some of the other essential genes involved in ovarian development include Wnt-4 and DAX-1<br />
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• Cortical cords extend from the surface of the developing ovary into the underlying mesenchyme during early fetal period<br />
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• As these cortical cords increase in size, primordial germ cells begin to arise> these then become primordial follicles> which contain an oogonium> proliferate and enter first meiotic division to for primary oocytes<br />
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• By the 10th week, ovaries are histologically identifiable<br />
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===Human Ovary Timeline===<br />
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• 24 days - intermediate mesoderm, pronephros primordium<br />
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• 28 days - mesonephros and mesonephric duct<br />
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• 35 days - uteric bud, metanephros, urogenital ridge<br />
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• 42 days - cloacal divison, gonadal primordium (indifferent)<br />
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• 49 days - paramesonephric duct, gonadal differentiation<br />
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• 56 days - paramesonephric duct fusion (female)<br />
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• 100 days - primary follicles (ovary)<br />
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Hill, M.A. (2014) Embryology Ovary Development. Retrieved October 7, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Ovary_Development<br />
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[[File:Historic-ovary.jpg]]<br />
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==Lab Assessment 9==<br />
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===Group 2===<br />
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The introduction to this page was will written and the information was clear and to the point. Each component of the renal system was mentioned in your group’s introduction which gave an overall/holistic preview of the information that is evidently discussed underneath. There is a developmental timeline showing the key events of renal development at the embryonic, fetal and post-natal stages. Perhaps consider presenting this information in a table. The historic findings section, however, was lacking information. This section needs to be further researched and added to make this project complete.<br />
Your choice of content, clear structure, headings and images is evident that your group is working well and have a good understanding of this topic area. However, there is no hand drawn image yet. The image chosen form Langman’s Medical Embryology is a great image to show as it demonstrates the progressive stages of kidney ascent, perhaps you could consider re-drawring that image rather than just immediately upload it from the textbook. Your descriptions and information presented can be understood at the peer level. It is both engaging and informative, well done!! There is also a good balance between text and images that are appealing for the reader. The information presented in the first half of your project is ample however this is not coherent with the second half of your project page, where descriptions are not as developed.<br />
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There is a great selection of images that are used in your group project. Most of these images are correctly cited and have been uploaded in the correct manner. Some images are just missing the student template image:{{Template:Student Image}}<br />
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You can view this in edit mode and add it to your images.<br />
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There are a great number of resources that are used in this project, and all your references are correctly cited. As your project is still underway, I am sure that you will add additional references and also make it one complete this at the end of your project.<br />
Overall, I enjoyed reading about the renal system on presented by your group and I am confident you will earn high marks for your project. Best of wishes group 2!<br />
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===Group 3===<br />
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Your introduction to the gastrointestinal system provided a clear overview of what your project is about. I think it would be a good idea to couple this introduction with an image that shows the pathway and divisions of the GIT. The timeline shown is fantastic, it is not only extensive, but it divides the GIT into regions of the foregut, midgut and hindgut as well as the weeks in which key development events take place. It is in simple, easy to read language, at an element of teaching at the peer level- great work! There is also a reference next to each of these events which reflects the amount of research that took place-well done guys! <br />
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Your page includes a table with statistics- the percentage of herniated foetuses which adds credibility to your work and gives the reader information on how frequent this abnormality occurs. Your section for current does not have a lot of information, there is only one reference available for your recent findings. This section of your project needs to be further researched before the submission date.<br />
There is more than one hand drawn image is which fantastic! The colours used for it are a bit too bright, however, this shouldn't be too difficult to change, perhaps just adjust the brightness of the picture on paint, or whichever program the picture opens up with on your computer (this is just a very minor critique. The fact that your group project has more than one student hand drawn image shows adherence to the requirement for the project guidelines. <br />
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It was great to see only one reference list, as opposed to different reference lists for each section in the project. Your reference list appears to be long, with 24 references however, 16 of these references part of the timeline. More research papers need to be included to make what is already an amazing project, better! <br />
A video of the GIT and the rotations that occur during development would be rotations would be great visual representation of this system due to the nature of its development course. Perhaps you could find one off YouTube or create one.<br />
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Overall, this is a good project page, well done group and best of wishes!<br />
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===Group 4===<br />
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Your group project is of excellent quality, there are just a few minor things to take in to consideration if you wish. <br />
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Firstly, well done in creating a timeline in a table format that seperates the key events that occur between male and female gonad development. This is exactly the type of information I wouldve expected to see if I was interested in looking up information about the differences between male and female internally and externally and when these events take place. There is, however, much information about the male in this table and not as much information as there is in the female. You might also like to consider selecting one type of font for your table, just so that it looks a little neater. <br />
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Your section of current research and findings looks fantastic, with a lot of text, but sadly not enough images! Good work though with the and drawn image! There are a few hand drawn images on this group project page so well done for that! There are a few parts in the project where an image still needs to be uploaded/formatted but it looks like you are aware of these things with mention of [draw image here] as an example. In this same section, there is a great number of dot points, perhaps try to part of it in paragraphs so that not all the information is simply presented in dot point form. You can tell you have done a lot of research here, so well done.<br />
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In the historic finding section, there is a lot of text and only one image (a hand draw one, which is really good!). However, the amount of text is not matched with a visual component such as more images, or a diagram or table. Perhaps increase the amount of visual things in this section so there is appropriate balance-awesome work really!<br />
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Great choice of a youtube video! It showed the different stages of gonad development, both at the indifferentiation stage and when the gonads differentiate, into male and female. However, the video is quite long, it is approximately 10 minutes long, would you perhaps consider a shorter video? or trimming the video down? With that being said, I do think it provides a great visual for the key developmental aspects, so great choice there!<br />
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The abnormalities section is well researched. The abnormalities are listed from the most common to those that are rare, that a great way of giving the reader a general idea of its frequency in society. There are any abnormalities described in this section, and information is presented equally for both sexes as well as abnormalities that affect both sexes. There is also an excellent hand drawn image from the textbook that is correctly cited and contains the appropriate copyright information as well permission for this image to be reused after 6 months.<br />
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One last thing, before submission place all your references in one reference list.<br />
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Well done project group 4! I enjoyed reading about your project. All the best!<br />
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===Group 5===<br />
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Group 5, you have a brilliant introduction, introducing the reader to what your page is about. Your introduction contains information for each of the parts involved in the integumentary system such as skin, glands, hair nails and teeth. There is a clear structure to your project with clear headings and sub-headings. This makes the reader find information about a particular part in your project more easily.<br />
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There is an extensive list of references, which demonstrates, a great effort towards researching your projects system. Some of the references however, need to be put into in the correct format. There are different reference lists under the different sections of your group project and as I understand why, I'm sure these are just small things that will be fixed before the final submission.<br />
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I have to commend you on your table, it is more than sufficient. It not only clear describes a clear transition from week to week changes in development of the integumentary system. The table however, needs to be reformatted to fit the window of the page and likewise, the pictures inside the table as there are too small to be seen without opening up the image. There are other images also on the page were too small such as "The stages of embryonic teeth development". These are just minor changes that need to be made before your groups final submission. <br />
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At the start of your project, all descriptions were matched with an image. This provided an appropriate balance between written text and visual representations. However, in the historic findings section, this balance was not seen as there are no images for this section. <br />
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Your page also contains information that is teaching at the peer level-well done guys.<br />
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Under your section of some recent findings, there are blocks of information in purple; I'm not sure as to the reasoning behind this, as the other parts in your project do not have the same background. <br />
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I particularly liked how in the introductory paragraph you mentioned what topics you will be covering; including abnormalities associated with the Integumentary system and delivered this information under the abnormalities section, where treatments and managements of these abnormalities were put forward! <br />
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Overall, good work guys!<br />
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===Group 6===<br />
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Great work, it looks like your group has a clear mindset and direction to where your group project is going, even if it is not there yet. One of the images next to the timeline section was too small to be view without actually opening up the actual image. There are a few images on your page, and also a few tables, perhaps uploading a few more images that correspond to the text would make your project page more visualling appealing. <br />
<br />
There is table in your introduction- Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and foetal development. This is a great way to summarise information you have discovered after your research. However, as there is only one line of information, the information you have gathered needs to be added in order to make your group page complete.<br />
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Under the heading of Pineal gland, there is a sub-section labelled 'timeline', however there are only three points under this and no time course, or time frame included. The timeline needs to be further developed. You may also consider putting this information into a table and referencing articles from which you found this information. <br />
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There is not a lot of information for abnormalities. Only an uncompleted table and a references list exist. This information needs to be filled out the sooner the better. There seems to be a sub-section about abnormalities for each endocrine organ, but this does not contain much information-see Pineal gland and Hypothalamus sections. Perhaps your group would consider, just having one section in your project for all the abnormalities associated with the endocrine system. <br />
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There are several reference lists within your group project page that need to be put together to create just one reference list, I understand why this is at the moment, just remember to change before your final group submission.<br />
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Overall, well done group 6!<br />
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===Group 7===<br />
Your group's project page has a good introduction with a description entailing what your page is about and the information your page covers.<br />
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There is a very good layout, with a combination of text, tables, dot points and images- well done!Some of the images however a slightly small (Images under Brain development) or too big (image under development during fetal period) and need to be reformatted. <br />
<br />
Whilst your group mentioned that the neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain), there was no mention of the different brain flexures in your project. This an important aspect of brain development as it divides the three primary vesicles into 5 secondary primary vesicles (which you did mention) and how the cephalic flexure separates the brain from the spinal cord. <br />
<br />
The images use in your project are excellent and provide a visual to the information that you describe. However, there are many images from your group project that are from the lecture notes, perhaps try and mix up your selection to incorporate images from other sources such as research articles on pubmed. There also appears to be an image deleted under the Abnormalites, and this formatting would need to be fixed up, but this is just a small thing.<br />
<br />
Well done for your extensive reference list that you have. Although it is split in respective parts of your project, under different headings, don't forget to make it into one before the final submission.<br />
<br />
===Group 8===<br />
<br />
The introduction to your page is extremely funny, but this is completely irrelevant to the project and should be taken out before you submit the assignment. There are long blocks of texts on the page, with no tables or any pictures sadly. There should be a some images/digarams/videos for each heading. There is a number of good headings, with information within that needs to be further developed. There is great potential for this group project to develop further. <br />
<br />
There is a Heading labelled, 'Muscle development general timeline' however, underneath this section, there is only a small paragraph with no timeline whatsoever. If you don't want to have a timeline in this section of your project, then remove the word 'timeline from this heading'. However, I think a timeline would be a great way to show an overview of the key events of the muscoskeletal system. <br />
<br />
There is an broad, and long section of information under "background embryonic development". Just remember that our projects are about fetal development and not the embryonic stage of the system our project is about. The time spent on writing this section could have been spent on working on other parts of the assignment that require greater attention.<br />
<br />
Towards the end of the references list, there are references that have not properly been citied. There also exists a format error in your reference list that would need to be fixed before the final group submission.<br />
<br />
<br />
==Lab Assessment 10==<br />
<br />
<pubmed>25324764</pubmed><br />
<br />
Amongst the five senses is vision. For one of the most important processes of development, visuomotor development of the eyes takes place at the embryonic and fetal stages but rapidly develops after birth. Although there may not be much visual stimuli inside the maternal environment, the foetus is still able to see as visually excitable cortical areas already exist before extrinsic stimuli are present. External stimuli for example, can be facial recognition or other visual cues. Fetal eye movements although observed in utero, there is no receptive brain activity detected from visual stimuli. Thus, the aim of this study was to make the link between the spontaneous eye movements that are observed and the signalling network back to the frontal cerebral areas of the brain.<br />
<br />
<br />
'''Research Methods'''<br />
<br />
In order for this research group to carry out their investigation, they selected seven foetuses between 30-36 weeks and mothers with an average age of 32.29 years. MRI imaging was conducted to ensure no pathological brain development existed and this consent was approved by from the maternal participants on behalf of the unborn fetus. <br />
<br />
The movements by the fetus were then tracked by fMRI and data was computed. As a result of this mapping, eye centre locations and lens centre locations were determined. Correspondingly, the head axis was defined as the symmetry axis between the two eyes. <br />
<br />
<br />
'''Research Findings'''<br />
<br />
After obtaining fMRI data and ICA information, the positions of the eyes were determined. The relationship of single-subject component time courses with the eye movement regressor was calculated. Four fetal eye movement patterns were initially characterized based on early ultrasound observations. Some of the results included:<br />
<br />
Type I eye movements were described as single, transient deviations consisting of a bulb deviation, and a slower return back to the resting position, single but prolonged eye movements <br />
<br />
Type II, complex sequences of eye movements to different directions without periodicity<br />
<br />
<br />
Sensory Notes page:<br />
https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_System_Development<br />
<br />
<br />
==Lab Assessment 11==<br />
<br />
<pubmed>19637940</pubmed><br />
<br />
<br />
Induced pluripotent stem cells (iPS) are stem cells that resemble embryonic stem cells (ES) because of their capacity to generate all cell types within the body. In this research paper, they examine whether a somatic cell, once returned to it pluripotent state can gain the ability to reprogram other somatic cells. By applying somatic cell nuclear transfer (SCNT) and reprogramming by cell fusion of two different cells and consequently two different genomes to create a hybrid. As expected and as in most cases the phenotype of the less differentiate fusion partner dominated the phenotypes of the more-differentiated partner. Thus embryonic cells belonging to the mouse have the ability to reprogram the somatic genome of human embryonic cells following both cell fusions of each species. Their findings concluded that indeed once the nucleus of somatic cell is reprogrammed, it possesses the capacity and pluirpotency to reprogram other somatic cells by cell fusion and it shares this trait with those of embryonic stem cells (ES).</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=User:Z3332339&diff=161210
User:Z3332339
2014-10-29T00:08:40Z
<p>Z3332339: /* Lab Attendance */</p>
<hr />
<div>{{StudentPage2014}} <br />
<br />
==Lab Attendance==<br />
Lab1 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 12:45, 6 August 2014 (EST)<br />
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<br />
http://www.ncbi.nlm.nih.gov/pubmed<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed PubMed]<br />
<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25084016 PMID25084016]<br />
<br />
<pubmed>25084016</pubmed><br />
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Lab2 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:13, 13 August 2014 (EST)<br />
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Lab 3 --[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:12, 20 August 2014 (EST)<br />
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Lab 4--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 27 August 2014 (EST)<br />
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Lab 5--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 3 September 2014 (EST)<br />
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Lab 6--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:12, 10 September 2014 (EST)<br />
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Lab 7--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:05, 17 September 2014 (EST)<br />
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Lab 8--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:24, 24 September 2014 (EST)<br />
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Lab 9--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:10, 8 October 2014 (EST)<br />
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Lab 10--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 12:05, 15 October 2014 (EST)<br />
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Lab 11--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:16, 22 October 2014 (EST)<br />
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Lab 12--[[User:Z3332339|Z3332339]] ([[User talk:Z3332339|talk]]) 11:08, 29 October 2014 (EST)<br />
<br />
== Lab Assessment 1==<br />
<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/24952156 PMID24952156]<br />
<br />
'''A role for carbohydrate recognition in mammalian sperm-egg binding''' <br />
The primary focus of this article is on the first stage of fertilization, the binding of sperm to the specialised extracellular matrix of the egg, known as the zona pelluicda (ZP). The article suggests that the mammalian egg cell has a specialised carbohydrate site on the ZP for which the sperm recognises and binds to, enabling the fusion of genetic information between these two gametes. <br />
<br />
The article explains how it was previously thought that data obtained from mouse sperm-egg interactions could explain human sperm-cell binding. However, recent research has suggested that the mouse model cannot be directly applied to the human model. Thus, this research paper investigates sperm-ZP interactions, using humans as the predominant model in finding the specific requirements for human sperm-egg binding which couldn’t previously be explained by the mouse model. <br />
<br />
This article also uses a review that focused on the identification of the egg binding proteins associated with the binding of human sperm to the egg. Their findings concluded identifying the role for carbohydrate recognition on the ZP. These carbohydrates have specific sequences that cause restriction of ZP glycosylation in humans that could not otherwise be explained in mouse and pig models or are not the same for humans. This finding suggests that the regulation of glycosylation could be directly correlated with the degree of organismal complexity. Evidence favouring this concept would require the sequencing of ZP glycoproteins from other mammals at different levels of the evolutionary ladder, which could be are areas of future directions for this research.<br />
<br />
<br />
[http://www.ncbi.nlm.nih.gov/pubmed/25044079 PMID25044079]<br />
<br />
'''Examining the temperature of embryo culture in in vitro fertilization: a randomized controlled trial comparing traditional core temperature (37°C) to a more physiologic, cooler temperature (36°C)'''<br />
<br />
The study undertaken in this article was to determine if better clinical outcomes of IVF resulted from embryo cultures in cooler temperatures (36 degrees) as oppose to the traditional core temperature of (37 degrees). <br />
<br />
The method of investigation: retrieving eight or more oocytes from a female of 42 years of age, with infertile couples (n=52). These mature oocytes were divided into two groups to be cultured at different temperatures; one group at 36 degrees, the other at 37 degrees. The rate of development and expansion of blastocysts (volume), fertilization, aneuploidy and sustained implantation were the factors measured to in order to determine which of these conditions clinically improved the environment best for embryonic development. This could potentially change the temperatures of which in vitro fertilization takes places in clinics in the future. <br />
<br />
However, the results concluded that IVF culture at 36 degrees does not improve the conditions for blastulation and pregnancy rates in human in IVF. Thus, maintaining the existing temperature or changing it to 26 degrees does not alter the effects or success of IVF.<br />
<br />
--[[User:Z8600021|Mark Hill]] These articles are good and your descriptions are appropriate. We will discuss in later tutorials how to format the referencing correctly. [[Help:Reference_Tutorial]] (5/5)<br />
<br />
==Lab Assessment 2==<br />
<br />
=='''Oocytes with Dark Zona Pelluica affect fertility'''==<br />
<br />
[[File:Oocytes with DZP demonstrate affect on fertility.png|600px]]<br />
<br />
<br />
Human mature oocytes with a normal (A) and dark (B) zona pelluicda. Oocytes with a DZP (dark zona pelluicda) have demonstrated a lower success of fertlization and implantation in clinical pregnancy rates in IVF/ICSI cycles. Patients with normal zona pellucida (NZP) were used as the control group.<br />
<br />
===Reference===<br />
<pubmed>24586757</pubmed>| [http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0089409 PLoS One.]<br />
<br />
[http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0089409#pone-0089409-g002 Figure 2. Human mature oocytes with a normal (A) and dark (B) zona pellucida.Scale bar (A, B): 100 µm. doi:10.1371/journal.pone.0089409.g002]<br />
<br />
<br />
Shi W, Xu B, Wu L-M, Jin R-T, Luan H-B, et al. (2014) Oocytes with a Dark Zona Pellucida Demonstrate Lower Fertilization, Implantation and Clinical Pregnancy Rates in IVF/ICSI Cycles. PLoS ONE 9(2): e89409. doi:10.1371/journal.pone.0089409<br />
<br />
===Copyright===<br />
<br />
© 2014 Shi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
<br />
--[[User:Z8600021|Mark Hill]] This is a good image for the assessment and I have made some minor changes to the information associated with the file. You do not need to include the copyright and student template on your page, just with the image. (5/5)<br />
<br />
{{Template:Student Image}}<br />
<br />
==Lab Assessment 3==<br />
===2.Identify Current Research, Models and Findings===<br />
<br />
<br />
===Physiological factors in fetal lung growth===<br />
<pubmed>3052746</pubmed><br />
<br />
<br />
This article looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite. It is crucial to the function of the neonatal lung because:<br />
<br />
A. Its high viscosity and low surface tension stabilize the diameter of the alveoli and prevent their collapse after each expiration. <br />
<br />
B. Because the alveoli remain partially open, they are expanded on inspiration with much less expenditure of energy. [ANAT 2241 LEC 11-Respriation]<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential. <br />
<br />
[this will be looked at further as the research project progresses]<br />
<br />
<br />
<br />
===Lung morphogenesis revisited: old facts, current ideas===<br />
<pubmed>11002333</pubmed><br />
<br />
<br />
Classical ideas -4 basic rules vs their review<br />
<br />
<br />
<br />
===Genetic control of lung development===<br />
<pubmed>12890942</pubmed><br />
<br />
<br />
Current concepts of lung development<br />
<br />
<br />
<br />
===Effects of hormones on fetal lung development===<br />
<pubmed>15550344</pubmed><br />
<br />
<br />
<br />
===The fetal respiratory system as target for antenatal therapy===<br />
<pubmed>24753844</pubmed><br />
<br />
<br />
--[[User:Z8600021|Mark Hill] These references are more than appropriate (5/5).<br />
<br />
==Lab Assessment 4==<br />
<br />
===1. An example of a use of Stem Cell Cord Therapy===<br />
<br />
<pubmed>25101638</pubmed><br />
<br />
Human mesenchymal stem cells MSCs (human embryonic tissue) have been used on animal models such as mice for their therapeutic qualities involved in regenerating liver tissue. This paper specifically looks at the possibility of using MSC to be used to treat degenerating organs after the discovering that MSC can be used as a substitute for liver acute failure on the mouse model. The human umbilical cord MSCs (hUCMSCs) have the capability to differentiate into hepatocyte-like cells due to their multipotence, meaning the that all the functions of the typical hepatocyte such as secretion of albumin and storage of glycogen can now be carried out from the hUCMSCs. <br />
<br />
<br />
To imitate the environment for hUCMSCs to proliferate and differentiate into functional hepatocyte-like cells (iHeps), hUCMSCs were exposed to the growth factors, cytokinesis and chemicals. The induced i-heps demonstrated similar morphology to that of human hepatocytes, however the more significant part was evaluating their hepatic functions. Demonstration of hepatocyte function of i-Heps in vitro, is summarised in their findings as they compared i-Heps to hUCMS.<br />
1) More glycogen was stored in i-Heps than in hUCMSC<br />
2) 12 times more urea was produced by i-Heps than hUCMSC <br />
3) lower levels of glycogen were stored in hUCMSC <br />
<br />
This has had a significant clinical research relevance in treating acute liver failure and the possibility of treating other diseases as well.<br />
<br />
===2.Vascular shunts present in the embryo but closed postnatally ===<br />
<br />
# The Foramen ovale -located between the right and left atrium.<br />
# The Ductus arteriosus - located between the pulmonary artery and descending aorta.<br />
# The Ductus venosus - located in the liver between the umbilical vein and IVC.<br />
<br />
<br />
==Lab Assessment 5==<br />
<br />
'''Abnormality of Respiratory development: Asthma'''<br />
<br />
<br />
Asthma is a disease that affects 10% of the population in Australia according to the Asthma organisation of Australia. <ref>http://www.asthmaaustralia.org.au/Statistics.aspx</ref>.This prevalence in Australia is significantly high compared to other countries. However, the cause for our high ranking amongst other countries is unknown. In this research paper, a strong association between low birth weight, short gestational age and fetal growth restriction is shown to influence the development of asthma in children.<br />
<br />
A primary part of their research involved a cohort study on infants born between 1979-2005, and following up during different stages of their development postnatally; 3 years old, first hospitalisation for asthma, 18th birthday etc. A majority of the subjects were hospitalized for asthma during their follow up that was consistent with their 3 findings that influenced infant hospitalisation because of the disease.<br />
<br />
One conclusion from the study was that pre-term neonates may have under developed lungs that are smaller than the fetuses who completed the full gestation period (38weeks). Incompetent lungs could be due to restricted growth factors, inhibiting full lung capacity. Fetuses that were born small yet completed the gestational period, were infants unaffected by asthma and hence hospitalisation from it. As predicted, the risk of hospitalization for childhood asthma was proportional to lower birth weights, with only 1kg making a remarkable difference. This was a similar case for shorter gestational age. <br />
<br />
===References===<br />
<references/><br />
<br />
<pubmed>24602245</pubmed><br />
<br />
<br />
<br />
==Lab Assessment 7==<br />
<br />
One of the most important developmental aspects of the male gonads is the descent of the testes. Recent research has discovered that the normal descent of the testes during male gonad development can be interrupted when exposed to paracetamol, aspirin, and Indomethacin (a nonsteroidal anti-inflammatory drug) causing cryptorchidism. Cryptorchidism is an abnormality of either unilateral or bilateral testicular descent, occurring in up to 30% premature and 3-4% term males. Descent may complete post-natally in the first year, failure to descend can result in sterility <ref>https://php.med.unsw.edu.au/embryology/index.php?title=File:Cryptorchidism.jpg.</ref> . The aim of this research article was to determine whether common analgesic (pain relief drugs as mentioned above) disrupted the morphology and endocrine function of the human testis <ref><pubmed>24030937</pubmed></ref> .<br />
<br />
Amongst the outcomes measured from comparing human fetal testes exposed to analgesic and those were not exposed to analgesic, were testosterone and the anti-Müllerian hormone. The number of testicular cells was then counted through histological and image analysis, as the testing of this occurred ''in vitro''. The conclusion from this research identified that when fetuses were exposed to analgesic from pregnancy this cause disturbances in the fetal testis. These disturbances increase when small, critical age windows, such as when male gonad development takes place.<br />
<br />
Data from a recent study of male human fetal (between 10 and 35 weeks) gonad position <ref>http://php.med.unsw.edu.au/embryology/index.php?title=BGD_Lecture_-_Sexual_Differentiation.</ref><br />
<br />
*10 to 23 weeks - (9.45%) had migrated from the abdomen and were situated in the inguinal canal<br />
*24 to 26 weeks - (57.9%) had migrated from the abdomen<br />
*27 to 29 weeks - (16.7%) had not descended to the scrotum<br />
<br />
Thus, what is advised by this article is a caution concerning consumption of analgesics such as aspirin, indomethacin, and paracetamol during pregnancy that may cause an inhibition of normal fetal testes morphology and endocrine function.<br />
<br />
===References===<br />
<references/><br />
<ref>https://php.med.unsw.edu.au/embryology/index.php?title=File:Cryptorchidism.jpg.</ref><br />
<ref>https://embryology.med.unsw.edu.au/embryology/index.php?title=BGD_Lecture_-_Sexual_Differentiation.</ref><br />
<ref>http://embryology.med.unsw.edu.au/embryology/index.php?title=ANAT2341_Lab_7.</ref><br />
<br />
<br />
The embryonic layers and tissues that contribute to developing teeth.<br />
The stages in tooth development include:<br />
<br />
*Lamina<br />
*Placode<br />
*Bud<br />
*Cap<br />
*Bell<br />
<br />
The tissues that contribute to developing teeth include:<br />
<br />
*Odontoblasts<br />
*Ameloblasts<br />
*Periodontal ligament<br />
<br />
==Lab Assessment 8==<br />
<br />
===Embryonic Development of the Ovary===<br />
<br />
====Indifferent Stage====<br />
<br />
Much of the gonad development between males and females is analogous during embryonic development. Differentiation of the gonads (testis or ovary) occur late in embryonic development. Sexual differentiation is determined early on, where double X chromosomes in embryo will trigger the female gonad development whereas, an inherent XY chromosome will determine that the sex of this embryo will be a male. More particularly, the expression of the SRY gene on the Y chromosome determines the gender of the conceptus and signals pathways for male gonad development. Thus, when the SRY gene is not expressed, the human embryo will follow the gonad development of females.<br />
<br />
Another contributing factor to gonad development after sex determining genes is hormone production. For example, at the urogenital sinus the presence dihyrdrotestosterone (DHT) determines males development and the absence of dihyrdrotestosterone (DHT) determines female development. <br />
<br />
====Differentiation Stage====<br />
<br />
• In the absence of the Y chromosome, female development occurs<br />
<br />
• somatic support cells differentiate into follicle cells (instead of sertoli cells in males)<br />
<br />
• From the intermediate mesoderm, the development of the Müllerian duct Müllerian duct persists and is stimulated to differentiate into the uterine tube, the uterus and the upper vagina. However, mesonephric ducts degenerate. The opposite occurs for the opposite sex.<br />
<br />
• Presence of dihyrdrotestosterone (DHT)<br />
<br />
• Absence of Anti- Müllerian hormone (AMH), since sertoli cells are not differentiated by SRY gene<br />
<br />
• Some of the other essential genes involved in ovarian development include Wnt-4 and DAX-1<br />
<br />
• Cortical cords extend from the surface of the developing ovary into the underlying mesenchyme during early fetal period<br />
<br />
• As these cortical cords increase in size, primordial germ cells begin to arise> these then become primordial follicles> which contain an oogonium> proliferate and enter first meiotic division to for primary oocytes<br />
<br />
• By the 10th week, ovaries are histologically identifiable<br />
<br />
===Human Ovary Timeline===<br />
<br />
<br />
• 24 days - intermediate mesoderm, pronephros primordium<br />
<br />
• 28 days - mesonephros and mesonephric duct<br />
<br />
• 35 days - uteric bud, metanephros, urogenital ridge<br />
<br />
• 42 days - cloacal divison, gonadal primordium (indifferent)<br />
<br />
• 49 days - paramesonephric duct, gonadal differentiation<br />
<br />
• 56 days - paramesonephric duct fusion (female)<br />
<br />
• 100 days - primary follicles (ovary)<br />
<br />
<br />
Hill, M.A. (2014) Embryology Ovary Development. Retrieved October 7, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Ovary_Development<br />
<br />
<br />
[[File:Historic-ovary.jpg]]<br />
<br />
<br />
==Lab Assessment 9==<br />
<br />
===Group 2===<br />
<br />
The introduction to this page was will written and the information was clear and to the point. Each component of the renal system was mentioned in your group’s introduction which gave an overall/holistic preview of the information that is evidently discussed underneath. There is a developmental timeline showing the key events of renal development at the embryonic, fetal and post-natal stages. Perhaps consider presenting this information in a table. The historic findings section, however, was lacking information. This section needs to be further researched and added to make this project complete.<br />
Your choice of content, clear structure, headings and images is evident that your group is working well and have a good understanding of this topic area. However, there is no hand drawn image yet. The image chosen form Langman’s Medical Embryology is a great image to show as it demonstrates the progressive stages of kidney ascent, perhaps you could consider re-drawring that image rather than just immediately upload it from the textbook. Your descriptions and information presented can be understood at the peer level. It is both engaging and informative, well done!! There is also a good balance between text and images that are appealing for the reader. The information presented in the first half of your project is ample however this is not coherent with the second half of your project page, where descriptions are not as developed.<br />
<br />
There is a great selection of images that are used in your group project. Most of these images are correctly cited and have been uploaded in the correct manner. Some images are just missing the student template image:{{Template:Student Image}}<br />
<br />
You can view this in edit mode and add it to your images.<br />
<br />
There are a great number of resources that are used in this project, and all your references are correctly cited. As your project is still underway, I am sure that you will add additional references and also make it one complete this at the end of your project.<br />
Overall, I enjoyed reading about the renal system on presented by your group and I am confident you will earn high marks for your project. Best of wishes group 2!<br />
<br />
===Group 3===<br />
<br />
Your introduction to the gastrointestinal system provided a clear overview of what your project is about. I think it would be a good idea to couple this introduction with an image that shows the pathway and divisions of the GIT. The timeline shown is fantastic, it is not only extensive, but it divides the GIT into regions of the foregut, midgut and hindgut as well as the weeks in which key development events take place. It is in simple, easy to read language, at an element of teaching at the peer level- great work! There is also a reference next to each of these events which reflects the amount of research that took place-well done guys! <br />
<br />
Your page includes a table with statistics- the percentage of herniated foetuses which adds credibility to your work and gives the reader information on how frequent this abnormality occurs. Your section for current does not have a lot of information, there is only one reference available for your recent findings. This section of your project needs to be further researched before the submission date.<br />
There is more than one hand drawn image is which fantastic! The colours used for it are a bit too bright, however, this shouldn't be too difficult to change, perhaps just adjust the brightness of the picture on paint, or whichever program the picture opens up with on your computer (this is just a very minor critique. The fact that your group project has more than one student hand drawn image shows adherence to the requirement for the project guidelines. <br />
<br />
It was great to see only one reference list, as opposed to different reference lists for each section in the project. Your reference list appears to be long, with 24 references however, 16 of these references part of the timeline. More research papers need to be included to make what is already an amazing project, better! <br />
A video of the GIT and the rotations that occur during development would be rotations would be great visual representation of this system due to the nature of its development course. Perhaps you could find one off YouTube or create one.<br />
<br />
Overall, this is a good project page, well done group and best of wishes!<br />
<br />
===Group 4===<br />
<br />
Your group project is of excellent quality, there are just a few minor things to take in to consideration if you wish. <br />
<br />
Firstly, well done in creating a timeline in a table format that seperates the key events that occur between male and female gonad development. This is exactly the type of information I wouldve expected to see if I was interested in looking up information about the differences between male and female internally and externally and when these events take place. There is, however, much information about the male in this table and not as much information as there is in the female. You might also like to consider selecting one type of font for your table, just so that it looks a little neater. <br />
<br />
Your section of current research and findings looks fantastic, with a lot of text, but sadly not enough images! Good work though with the and drawn image! There are a few hand drawn images on this group project page so well done for that! There are a few parts in the project where an image still needs to be uploaded/formatted but it looks like you are aware of these things with mention of [draw image here] as an example. In this same section, there is a great number of dot points, perhaps try to part of it in paragraphs so that not all the information is simply presented in dot point form. You can tell you have done a lot of research here, so well done.<br />
<br />
In the historic finding section, there is a lot of text and only one image (a hand draw one, which is really good!). However, the amount of text is not matched with a visual component such as more images, or a diagram or table. Perhaps increase the amount of visual things in this section so there is appropriate balance-awesome work really!<br />
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Great choice of a youtube video! It showed the different stages of gonad development, both at the indifferentiation stage and when the gonads differentiate, into male and female. However, the video is quite long, it is approximately 10 minutes long, would you perhaps consider a shorter video? or trimming the video down? With that being said, I do think it provides a great visual for the key developmental aspects, so great choice there!<br />
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The abnormalities section is well researched. The abnormalities are listed from the most common to those that are rare, that a great way of giving the reader a general idea of its frequency in society. There are any abnormalities described in this section, and information is presented equally for both sexes as well as abnormalities that affect both sexes. There is also an excellent hand drawn image from the textbook that is correctly cited and contains the appropriate copyright information as well permission for this image to be reused after 6 months.<br />
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One last thing, before submission place all your references in one reference list.<br />
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Well done project group 4! I enjoyed reading about your project. All the best!<br />
<br />
===Group 5===<br />
<br />
Group 5, you have a brilliant introduction, introducing the reader to what your page is about. Your introduction contains information for each of the parts involved in the integumentary system such as skin, glands, hair nails and teeth. There is a clear structure to your project with clear headings and sub-headings. This makes the reader find information about a particular part in your project more easily.<br />
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There is an extensive list of references, which demonstrates, a great effort towards researching your projects system. Some of the references however, need to be put into in the correct format. There are different reference lists under the different sections of your group project and as I understand why, I'm sure these are just small things that will be fixed before the final submission.<br />
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I have to commend you on your table, it is more than sufficient. It not only clear describes a clear transition from week to week changes in development of the integumentary system. The table however, needs to be reformatted to fit the window of the page and likewise, the pictures inside the table as there are too small to be seen without opening up the image. There are other images also on the page were too small such as "The stages of embryonic teeth development". These are just minor changes that need to be made before your groups final submission. <br />
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At the start of your project, all descriptions were matched with an image. This provided an appropriate balance between written text and visual representations. However, in the historic findings section, this balance was not seen as there are no images for this section. <br />
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Your page also contains information that is teaching at the peer level-well done guys.<br />
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Under your section of some recent findings, there are blocks of information in purple; I'm not sure as to the reasoning behind this, as the other parts in your project do not have the same background. <br />
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I particularly liked how in the introductory paragraph you mentioned what topics you will be covering; including abnormalities associated with the Integumentary system and delivered this information under the abnormalities section, where treatments and managements of these abnormalities were put forward! <br />
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Overall, good work guys!<br />
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===Group 6===<br />
<br />
Great work, it looks like your group has a clear mindset and direction to where your group project is going, even if it is not there yet. One of the images next to the timeline section was too small to be view without actually opening up the actual image. There are a few images on your page, and also a few tables, perhaps uploading a few more images that correspond to the text would make your project page more visualling appealing. <br />
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There is table in your introduction- Table 1. Summarises the hormones released by the human pineal gland and their role in embryonic and foetal development. This is a great way to summarise information you have discovered after your research. However, as there is only one line of information, the information you have gathered needs to be added in order to make your group page complete.<br />
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Under the heading of Pineal gland, there is a sub-section labelled 'timeline', however there are only three points under this and no time course, or time frame included. The timeline needs to be further developed. You may also consider putting this information into a table and referencing articles from which you found this information. <br />
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There is not a lot of information for abnormalities. Only an uncompleted table and a references list exist. This information needs to be filled out the sooner the better. There seems to be a sub-section about abnormalities for each endocrine organ, but this does not contain much information-see Pineal gland and Hypothalamus sections. Perhaps your group would consider, just having one section in your project for all the abnormalities associated with the endocrine system. <br />
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There are several reference lists within your group project page that need to be put together to create just one reference list, I understand why this is at the moment, just remember to change before your final group submission.<br />
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Overall, well done group 6!<br />
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===Group 7===<br />
Your group's project page has a good introduction with a description entailing what your page is about and the information your page covers.<br />
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There is a very good layout, with a combination of text, tables, dot points and images- well done!Some of the images however a slightly small (Images under Brain development) or too big (image under development during fetal period) and need to be reformatted. <br />
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Whilst your group mentioned that the neural tube differentiates into the proencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain), there was no mention of the different brain flexures in your project. This an important aspect of brain development as it divides the three primary vesicles into 5 secondary primary vesicles (which you did mention) and how the cephalic flexure separates the brain from the spinal cord. <br />
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The images use in your project are excellent and provide a visual to the information that you describe. However, there are many images from your group project that are from the lecture notes, perhaps try and mix up your selection to incorporate images from other sources such as research articles on pubmed. There also appears to be an image deleted under the Abnormalites, and this formatting would need to be fixed up, but this is just a small thing.<br />
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Well done for your extensive reference list that you have. Although it is split in respective parts of your project, under different headings, don't forget to make it into one before the final submission.<br />
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===Group 8===<br />
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The introduction to your page is extremely funny, but this is completely irrelevant to the project and should be taken out before you submit the assignment. There are long blocks of texts on the page, with no tables or any pictures sadly. There should be a some images/digarams/videos for each heading. There is a number of good headings, with information within that needs to be further developed. There is great potential for this group project to develop further. <br />
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There is a Heading labelled, 'Muscle development general timeline' however, underneath this section, there is only a small paragraph with no timeline whatsoever. If you don't want to have a timeline in this section of your project, then remove the word 'timeline from this heading'. However, I think a timeline would be a great way to show an overview of the key events of the muscoskeletal system. <br />
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There is an broad, and long section of information under "background embryonic development". Just remember that our projects are about fetal development and not the embryonic stage of the system our project is about. The time spent on writing this section could have been spent on working on other parts of the assignment that require greater attention.<br />
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Towards the end of the references list, there are references that have not properly been citied. There also exists a format error in your reference list that would need to be fixed before the final group submission.<br />
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==Lab Assessment 10==<br />
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<pubmed>25324764</pubmed><br />
<br />
Amongst the five senses is vision. For one of the most important processes of development, visuomotor development of the eyes takes place at the embryonic and fetal stages but rapidly develops after birth. Although there may not be much visual stimuli inside the maternal environment, the foetus is still able to see as visually excitable cortical areas already exist before extrinsic stimuli are present. External stimuli for example, can be facial recognition or other visual cues. Fetal eye movements although observed in utero, there is no receptive brain activity detected from visual stimuli. Thus, the aim of this study was to make the link between the spontaneous eye movements that are observed and the signalling network back to the frontal cerebral areas of the brain.<br />
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<br />
'''Research Methods'''<br />
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In order for this research group to carry out their investigation, they selected seven foetuses between 30-36 weeks and mothers with an average age of 32.29 years. MRI imaging was conducted to ensure no pathological brain development existed and this consent was approved by from the maternal participants on behalf of the unborn fetus. <br />
<br />
The movements by the fetus were then tracked by fMRI and data was computed. As a result of this mapping, eye centre locations and lens centre locations were determined. Correspondingly, the head axis was defined as the symmetry axis between the two eyes. <br />
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<br />
'''Research Findings'''<br />
<br />
After obtaining fMRI data and ICA information, the positions of the eyes were determined. The relationship of single-subject component time courses with the eye movement regressor was calculated. Four fetal eye movement patterns were initially characterized based on early ultrasound observations. Some of the results included:<br />
<br />
Type I eye movements were described as single, transient deviations consisting of a bulb deviation, and a slower return back to the resting position, single but prolonged eye movements <br />
<br />
Type II, complex sequences of eye movements to different directions without periodicity<br />
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<br />
Sensory Notes page:<br />
https://embryology.med.unsw.edu.au/embryology/index.php/Sensory_System_Development</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159950
2014 Group Project 1
2014-10-24T07:14:03Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
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<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
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The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
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This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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<br />
ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
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<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
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[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24004663</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung.<br />
<br />
• The high concentrations of FGF10 at the distal tip of the lung bud would initiate growth in that direction and thus elongate the tube in that direction. <br />
<br />
<br />
• As signalling is controlled for all lung branching, a split in FGF10 would result in terminal branching, and initation of lateral branching results. See c, d, e on the image<br />
<br />
<br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159944
2014 Group Project 1
2014-10-24T07:10:13Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24004663</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
• Assignalling is controlled for all lung branchin, a spilt in FGF10 would result in terminal branching, and initation of lateral branching results. See c, d, e on the left of image<br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159932
2014 Group Project 1
2014-10-24T07:04:15Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24004663</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
• The high concentrations of FGF10 at the distal tip of the lung bud would initiate growth in that direction and thus elongate the tube in that direction. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159923
2014 Group Project 1
2014-10-24T07:00:59Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24004663</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159914
2014 Group Project 1
2014-10-24T06:51:07Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
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|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Historic findings==<br />
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Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
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[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
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|}<br />
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==Current Understandings and Areas of Research==<br />
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The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
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'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
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'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
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'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
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Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
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'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
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|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
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[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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|}<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
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<br />
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• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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==2. '''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
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[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
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[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
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<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
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A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
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==Abnormalities==<br />
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As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
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===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159908
2014 Group Project 1
2014-10-24T06:48:26Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|325px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159896
2014 Group Project 1
2014-10-24T06:46:16Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|300px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159887
2014 Group Project 1
2014-10-24T06:43:10Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
<br />
<br />
<br />
<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159881
2014 Group Project 1
2014-10-24T06:35:21Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159878
2014 Group Project 1
2014-10-24T06:32:32Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|left|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|right|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159869
2014 Group Project 1
2014-10-24T06:28:57Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• [[File:Lung Fgf10 expression cartoon.jpg|right|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|left|400px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159866
2014 Group Project 1
2014-10-24T06:26:11Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg|centre|800px]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• [[File:Lung Fgf10 expression cartoon.jpg|right|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• [[File:Signalling factors in lung branching cartoon.png|left|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
[[File:Figure5-1.jpg|left|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development <br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159791
2014 Group Project 1
2014-10-24T06:04:11Z
<p>Z3332339: /* Respiratory */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the historic understandings of the respiratory system followed by an overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• [[File:Lung Fgf10 expression cartoon.jpg|right|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
==References==<br />
<references/></div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159764
2014 Group Project 1
2014-10-24T05:54:31Z
<p>Z3332339: /* Respiratory */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
[[File:3D model of the air way tree.jpg]]<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system, the lung. It places particular emphasis on the historic understandings of the respiratory system followed by an overview of fetal respiratory development. Discussion of current and historic findings during the fetal development of the respiratory system will also be elaborated on. Unfortunately, during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this, there will be a detailed explanation of abnormalities that we find relevant to this system to conclude. <br />
<br />
==Historic findings==<br />
<br />
Historic knowledge of the shifts in understanding of the respiratory development during the fetal stage is essential for robust appreciation of current accepted ideas of how this system comes to be in the human body. Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since before 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px|Historic image of the human embryo]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|200px|thumb|William Harvey (1578-1657)]]William Harvey discovered that the lungs were not the organ responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs, which was later discovered to be what we know today as surfactant, was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Hummer et al discovered that there occurred a reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth. This experiment was initially performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
Current knowledge of the development of the respiratory system portrays how understanding has advanced over time, from what was historically known about the system until what is known today. The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
The development of the respiratory system is one of the most crucial for the survival of the neonate, and hence it is a system that is highly studied. Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• [[File:Lung Fgf10 expression cartoon.jpg|right|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
• A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Abnormalities==<br />
<br />
As mentioned earlier, the development of the respiratory system in the fetus is one that has been known for many years dating back into history, and one that is still currently studied today. However, despite knowledge of respiratory system development being well understood, unfortunately, there still occurs a myriad of abnormalities in the neonate due to complications in development during the fetal stages of the developing human. In this section, we will discuss some of the primary abnormalities that is found in respect to the development of the respiratory system in the fetus.<br />
<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
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File:3D model of the air way tree.jpg
2014-10-24T05:52:42Z
<p>Z3332339: ==3D model of the air way tree large==
A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral vie...</p>
<hr />
<div>==3D model of the air way tree large==<br />
<br />
A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view<br />
<br />
==Adapted Image Source==<br />
<br />
Kitaoka H, Takaki R, Suki B. 1999. A three-dimensional model of the human airway tree. J. Appl. Physiol. 87, 2207–2217<br />
<br />
===Reference===<br />
<br />
Iber, D. and Menshykau, D. (2013). The control of branching morphogenesis. Open biology, 3(9), p.130088.<br />
<br />
http://rsob.royalsocietypublishing.org/content/3/9/130088<br />
<br />
===Copyright===<br />
© 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.</div>
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<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
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During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
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|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
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:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
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'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
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'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
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'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
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Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
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'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
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|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
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• [[File:Lung Fgf10 expression cartoon.jpg|right|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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|}<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
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• A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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==2. '''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
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::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
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[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
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The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
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::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
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A Comparison of lung development stages in the human and rabbit with their relationship towards gestational length<br />
can be found in Figure 1 of this article<br />
[http://www.formatex.org/microscopy3/pdf/pp417-425.pdf]<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein<br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159650
2014 Group Project 1
2014-10-24T05:15:39Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159611
2014 Group Project 1
2014-10-24T05:05:38Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH) <ref><pubmed>22359491</pubmed></ref><ref>,<pubmed>24004663</pubmed></ref>. Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159599
2014 Group Project 1
2014-10-24T05:01:53Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<ref><pubmed>22844507</pubmed></ref><br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159581
2014 Group Project 1
2014-10-24T04:50:13Z
<p>Z3332339: /* 1. The Conducting system - The respiratory network */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. [[File:Respiratorysystem2.png|thumb|550px|'''Embryonic Origins of Respiratory System.''']] The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation<br />
<br />
'''a) Domain branching''': In this type of mode, the respiratory network develops and continues to grow in a direction perpendicular to the future trachea. New lung bud formations become apparent appear on either side of the stalk. The most recent lung buds that are formed are shown in lighter colors, typically where outgrowths are observed. <br />
<br />
'''b) Planar bifurcation:''' these types of bifurcations form the thin edges of the lobes<br />
<br />
'''c)Orthogonal bifurcation:''' this type of bifurcation creates the lobe surfaces and fill the interior part of the respiratory system with the diaphragm, lies beneath. <br />
<br />
Note both b) and c)as the name suggests, these branching models are responsible for bifurcating the airways in consecutive rounds of tubular divisions<br />
<br />
'''d) Trifucation''': Researches have recently identified that this mode of branching is responsible for the backbone of the respiratory tree<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159443
2014 Group Project 1
2014-10-24T03:51:22Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
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{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
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:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
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{|<br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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{|<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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==2. '''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
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::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
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[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
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The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
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::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations <ref>http://www.oneofus.eu/wp-content/uploads/2014/06/One-of-Us.pdf</ref><br />
::• Cost effective<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
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===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
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===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
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===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
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*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
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===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
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==References==<br />
<references/><br />
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==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159428
2014 Group Project 1
2014-10-24T03:47:07Z
<p>Z3332339: /* Current Understandings and Areas of Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
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This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
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==Historic findings==<br />
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Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
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[[File:Bailey282.jpg|center|500px]]<br />
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{|<br />
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{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
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|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit).<br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations<br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159401
2014 Group Project 1
2014-10-24T03:44:07Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
==Development of the Respiratory system Overview==<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
[[File:Mouse.jpg|300px|right|thumb|The mouse-The most popular used animal model in today's research]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations<br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159341
2014 Group Project 1
2014-10-24T03:34:23Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.[[File:Mouse.jpg]]<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations<br />
::• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159320
2014 Group Project 1
2014-10-24T03:29:28Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
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The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
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This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
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During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
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|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
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:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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|}<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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==2. '''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
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::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
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The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
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::• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
::• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development [[File:Figure5-1.jpg|thumb| A complete diploid set of metaphase chromosomes from the laboratory mouse (Mus musculus) is shown.]]<br />
::• Ethical considerations<br />
::• Cost effective<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159296
2014 Group Project 1
2014-10-24T03:25:41Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
• The mouse reproduces quickly (in 21 days) <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
• Mouse generate many offspring. Anywhere between 8-20 at one time easily <ref>https://embryology.med.unsw.edu.au/embryology/index.php/Mouse_Development</ref><br />
• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development<br />
• Ethical considerations<br />
• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159272
2014 Group Project 1
2014-10-24T03:22:27Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange. The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
<br />
<br />
The reason why these animal models are currently used in research is for a number of reasons. Below is a list of reasons why the mouse model is widely used as part of research within the scientific community:<br />
<br />
• The mouse reproduces quickly (in 21 days)<br />
• Mouse generate many offspring. Anywhere between 8-20 at one time easily<br />
• Have similar genomic patterns which can be used as model to explain human embryonic and fetal development<br />
• Ethical considerations<br />
• Cost effective<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159230
2014 Group Project 1
2014-10-24T03:17:51Z
<p>Z3332339: /* Current Models */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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|}<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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==2. '''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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When considering models of research for analysing human development, animals such as the zebrafish, rabbit and mouse are most popular. These models have been used as part of research for scientists to study how different animals can be used to mimics the way the lung is developed in humans. These models have been chosen for various reasons, their genomic patterns, however, are the main reason. For example, at around E16.5 in the mouse, lung development switches from branching morphogenesis to the canalicular and saccular stages <ref><pubmed>18654673</pubmed></ref> . These, in turn, lead to the final process of alveologenesis that generates the functional units for gas exchange . The timing of alveolar development varies between species. In mice it occurs postnatally (∼P5–30), but in humans few alveoli have formed before birth and the process continues for many months- years afterwards.<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
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===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
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===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
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===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159188
2014 Group Project 1
2014-10-24T03:13:18Z
<p>Z3332339: /* 2. The Functional Unit-Alveolus */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::B) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159146
2014 Group Project 1
2014-10-24T03:04:56Z
<p>Z3332339: /* The Functional Unit-Alveolus */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
==1. '''The Conducting system''' - The respiratory network==<br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
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<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
==2. '''The Functional Unit'''-Alveolus==<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::b) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159131
2014 Group Project 1
2014-10-24T03:02:34Z
<p>Z3332339: /* Current Understandings and Areas of Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
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{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
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|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
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|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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==1. '''The Conducting system''' - The respiratory network==<br />
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{|<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
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:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
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{|<br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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{|<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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=='''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
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::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
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::::::b) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
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===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
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===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
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===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
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*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
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===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
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==References==<br />
<references/><br />
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==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159125
2014 Group Project 1
2014-10-24T02:59:58Z
<p>Z3332339: /* Current Understandings and Areas of Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
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This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
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==Historic findings==<br />
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Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
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[[File:Bailey282.jpg|center|500px]]<br />
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{|<br />
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{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
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|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
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|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
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|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
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|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
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|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
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|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
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|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
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=== Overview===<br />
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The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
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The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
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This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
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During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
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|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
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==Current Understandings and Areas of Research==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
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1. '''The Conducting system''' - The respiratory network<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
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:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
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{|<br />
|-bgcolor="E0 FF FF"<br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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|}<br />
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{|<br />
|-bgcolor="CEDFF2"<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
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::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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=='''The Functional Unit'''-Alveolus==<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
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• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
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• This article <ref><pubmed>24429276</pubmed></ref> looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and especially post-natally (Type 2alveolar cells) because <ref><pubmed>24058167</pubmed></ref>:<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
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::::::b) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
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==Current Models==<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
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NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
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Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
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===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
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===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159110
2014 Group Project 1
2014-10-24T02:53:49Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Understandings and Areas of Research==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
<br />
• This article looks at the current findings of different physiological factors that affect normal neonatal, functioning lungs upon during fetal development. The size of the paired organ to be able to exchange carbon dioxide with oxygen for the very first time at birth, is crucial to be able to withstand that pressure. As we know surfactant, is a lipid-protein composite that aids in this process. Both these epithelial cells that lines this tract a play important role and crucial to the function of the lung prior to birth and after (Type2) because<br />
<br />
::::::A) Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
::::::b) Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
However, current research suggests that the production of surfactant which is reliant on hormonal factors, have little influence on fetal lung growth. In contrast, the following physiological lung growth factors were found to permit the lungs to express their inherent growth potential.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300x230px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300x230px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159053
2014 Group Project 1
2014-10-24T02:35:57Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
• It was previously thought alveolar type I arise from type II cells but recent studies propose otherwise. By using molecular markers on the mouse model, this research <ref><pubmed>24499815</pubmed></ref> concludes that during development Type I and II cells arise directly from a bipotent progenitor, whereas after birth new Type I derive from rare, self-renewing, long-lived, mature Type II cells that produce slowly expanding clonal foci of alveolar renewal. Mapping alveolar cell locations is important for cancer treatment for patients.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|framed|right|300px|'''Postmortem revealing congenital laryngeal atresia.''']]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|framed|right|300px|'''Laryngeal atresia caused by Congenital High Airway Obstruction with hyperechoic lungs.''']]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs, subglottic stenosis, inversion of the diaphragm and hyperechoism of the lungs<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159044
2014 Group Project 1
2014-10-24T02:32:41Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
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{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
<br />
<br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
<br />
<br />
<br />
<br />
<br />
===Lung Development Stages===<br />
<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
<br />
<br />
[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
<br />
• Two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
• Although the first breath the newborn takes is after existing the birth canal, a recent article suggests that the two types of alveolar cells only appear to be mature 1 day prior to birth, when the distal tube dilates. <ref><pubmed>24499815</pubmed></ref>. This is a major concern for preterm infants, who many not have complete developed airways by the time that the new infant is born. This can lead to serious diseases including Idiopathic Pulmonary Fibrosis and Respiratory Distress Syndrome (For more information about this visit Newborn Respiratory Distress Syndrome under the "Abnormalities" section of this page)<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|right|300px|Postmortem revealing congenital laryngeal atresia]]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|right|300px]]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
[[File:CHAOS.jpeg|right|300px|Laryngeal Atresia caused by Congenital High Airway Obstruction Syndrome]]Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=159038
2014 Group Project 1
2014-10-24T02:28:34Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Year <br />
!align="center" valign="center"|Historic findings<br />
|-<br />
|align="center" valign="center"|400-300BC<br />
|align="center" valign="center"|Hippocrates acknowledged the role of spine deformities in leading to dysfunctional lung development and respiration. This deformity was later identified as scoliosis. <ref name="PMID5118050"><pubmed>5118050</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1628<br />
|align="center" valign="center"|[[File:William Harvey.jpg|400px|thumb|"William Harvey"]]William Harvey discovered that the lungs were not responsible for blood flow throughout the body, contrary to popular belief at the time. <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1661<br />
|align="center" valign="center"|[[File:Lung_historical_image.PNG|400px|thumb|"Historical image of lung development"]]Marcello Malpighi was an Italian scientist who contributed greatly to medicine, particularly the understanding of anatomy. He was a pioneer biologist to utilise newly invented microscopes to closely observe the human body. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli of the lung. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref> <ref name="PMID1399659"><pubmed>1399659</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Early 1900s<br />
|align="center" valign="center"|Studies specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
|-<br />
|align="center" valign="center"|1902<br />
|align="center" valign="center"|J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
|-<br />
|align="center" valign="center"|1929<br />
|align="center" valign="center"|The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
|-<br />
|align="center" valign="center"|1954<br />
|align="center" valign="center"|Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>.<br />
|-<br />
|align="center" valign="center"|1959<br />
|align="center" valign="center"|The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
|-<br />
|align="center" valign="center"|1963<br />
|align="center" valign="center"|Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|align="center" valign="center"|1994<br />
|align="center" valign="center"|Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref><br />
|-<br />
|}<br />
|}<br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
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During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
[[File:Oral cavity.png|thumb|right|550px|'''The development of the larynx from the 4th and 6th pharyngeal arches''']]<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Expression of Tbx4 and Tbx5 in the developing lung and trachea''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS [[File:4 subdivisons.jpg|thumb|right|550px|'''The four significant divisions in the respiratory system and the change in epithelium within their regions. ''']]<br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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<br />
===Lung Development Stages===<br />
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<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"| [[File:Lung bud.png|thumb|right|'''Image of newly formed lung bud''']] Lung buds would have formed as well as the lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermal derived epithelium that differentiates into respiratory epithelium, these line the airways and specialised epithelium like the on on the alveoli. <br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include, the formation of extensive airway branching of about 14 or more generations of branching, resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> The differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increases the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
|}<br />
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[[File:Lung development overiview.png|thumb|center|550px|'''An overview of the development of the respiratory system from the embryonic to fetal stage''']]<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
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Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
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• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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2. '''The Functional Unit'''-Alveolus<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named '''alveolar differentiation'''. There are two types of epithelial cells that typically line this tract and both play important role. These two types are described below and provide important background information for the modern research today.<br />
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• Two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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==Current Models==<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency - caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
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===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
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===Laryngeal Atresia===<br />
[[File:LaryngealAtresia.jpg|right|300px|Postmortem revealing congenital laryngeal atresia]]Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
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===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
[[File:CHAOS.jpeg|right|300px]]Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
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===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
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===Congenital Pulmonary Airway Malformation===<br />
[[File:CHAOS.jpeg|right|300px|Laryngeal Atresia caused by Congenital High Airway Obstruction Syndrome]]Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
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===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
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==References==<br />
<references/><br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157901
2014 Group Project 1
2014-10-23T16:08:58Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
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The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
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This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
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=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
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The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS <br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
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===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
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==Current Research and Direction of Future Areas of Investigation==<br />
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<iframe width="420" height="315" src="//www.youtube.com/embed/iktuxwfGpWE" frameborder="0" allowfullscreen></iframe><br />
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Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
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# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
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Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
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By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
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|}<br />
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2. '''The Functional Unit'''-Alveolus<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
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==Animal Models==<br />
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<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
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*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
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*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
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*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
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*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157895
2014 Group Project 1
2014-10-23T16:03:07Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157886
2014 Group Project 1
2014-10-23T16:00:28Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
{|<br />
|-bgcolor="CEDFF2"<br />
|<br />
<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
|}<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157880
2014 Group Project 1
2014-10-23T15:56:51Z
<p>Z3332339: /* Current Research and Direction of Future Areas of Investigation */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157877
2014 Group Project 1
2014-10-23T15:54:24Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Current Research and Direction of Future Areas of Investigation==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
{|<br />
|-bgcolor="lavenderblush"<br />
|<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
|}<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157865
2014 Group Project 1
2014-10-23T15:47:43Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Understanding of Current and Direction of Future Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
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<br />
{|<br />
|-bgcolor="E0 FF FF"<br />
|<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
|}<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
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2. '''The Functional Unit'''-Alveolus<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
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===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
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===References===<br />
<references/><br />
<br />
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==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157862
2014 Group Project 1
2014-10-23T15:44:46Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
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The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Understanding of Current and Direction of Future Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|275px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157859
2014 Group Project 1
2014-10-23T15:40:44Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
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<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
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The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
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The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
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ORAL CAVITY<br />
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The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
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LARYNX<br />
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The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
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TRACHEA <br />
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The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
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BRONCHI<br />
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The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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BRONCHIOLES<br />
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By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
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=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
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TERMINAL BRONCHIOLES<br />
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Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLAR DUCTS <br />
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The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
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ALVEOLI<br />
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The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Understanding of Current and Direction of Future Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
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1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
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• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
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[[File:Lung Fgf10 expression cartoon.jpg|centre|400px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
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• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
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From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
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::::::::::::::Slow growth factors----> bifurcated branching <br />
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[[File:Signalling factors in lung branching cartoon.png|right|425px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
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2. '''The Functional Unit'''-Alveolus<br />
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At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
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==Current Models==<br />
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==Animal Models==<br />
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[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
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==Historic findings==<br />
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Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
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*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
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[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
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'''Alveoli formation'''<br />
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*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
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*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
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*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
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*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
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==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
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The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
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===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
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*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
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===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157856
2014 Group Project 1
2014-10-23T15:37:49Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Understanding of Current and Direction of Future Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|400px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
<br />
[[File:Signalling factors in lung branching cartoon.png|right|450px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
Z3332339
https://embryology.med.unsw.edu.au/embryology/index.php?title=2014_Group_Project_1&diff=157850
2014 Group Project 1
2014-10-23T15:34:46Z
<p>Z3332339: /* Understanding of Current and Direction of Future Research */</p>
<hr />
<div>{{ANAT2341Project2014header}}<br />
<br />
=Respiratory =<br />
<br />
==Introduction==<br />
<br />
This page focuses on the development of the respiratory system during the fetal stage, exploring the two significant zones and the major organ of the respiratory system,the lung. This page emphasis further on the lung development, current and historic findings during the fetal development of the respiratory system.<br />
Unfortunately during the fetal development of the respiratory system, some things may go wrong leading to abnormalities in this important system. In respect to this there will be great mention of some abnormalities in detail. <br />
<br />
=== Overview===<br />
<br />
The respiratory system consists of organs and tissues that assist in breathing. Lungs are the most important organ for respiration. Humans have two lungs, a left and a right lung both located in the chest covered by many tissue, muscles and bones to protect them. The purpose of respiratory system is for gas exchange to occur, gas exchange is the removal of carbon dioxide and intake of oxygen into the lungs. Gas exchange is imperative for the function of life as oxygen is needed to working muscles.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
<br />
The respiratory system starts developing at week 4 of the embryo and a great deal of the development continues to take place in the fetal stage. A substantial portion of the respiratory system is formed by germ layer endoderm. The lung buds are lined by epithelium derived from the endodermal layer which later on differentiates into the respiratory epithelium. Nerves and neural innervations of the lungs are derived from ectoderm, on the other hand splanchnic mesoderm contributes to the pulmonary blood vessels, smooth muscle,cartilage and connective tissue.<br />
<br />
This system has many airways that allows the movement of air from nose or mouth to the lungs. Some of the airways include;<br />
*Nose (including the nasal cavity)<br />
*Mouth <br />
*Larynx <br />
*Trachea<br />
*Bronchi and their branches <br />
<br />
During the embryonic and fetal stage the respiratory system is developing. The embryonic stage is the first 1-8 weeks and anything after that until about week 37 or birth . However the respiratory system does not carry out gas exchange until birth. Whilst the embryo or fetus is in the mother, gas exchange occurs through the placenta. Once born the lungs of the new born are drained and are filled up with air automatically. The lungs do not inflate completely until about 2 weeks of the new born. The surfactant in each alveoli assists in keeping the lungs open and prevents them from collapsing.<ref>Cite this page: (2014) National Heart, Lung, and Blood Institute Health. Retrieved 20 September, 2014, from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063039/</ref><br />
<br />
The respiratory tract is divided into two main parts; the conducting zone and the respiratory zone.<br />
<br />
=== Development of the Conducting Zone===<br />
<br />
The conducting zone is made up nose to bronchioles, the main function is to filter, warm, and moisten air and conduct it into the lung. The conducting zone includes the nose, pharynx, larynx, trachea, bronchi and bronchioles. Nares are the opening into the nose and are where nasal cavities are lined with cilia, mucous membrane and consists of blood filled capillaries. <br />
<br />
<br />
ORAL CAVITY<br />
<br />
The oral cavity is formed by the stomodeum, which is the depression in the embryo located between the brain and the pericardium. This depression is known as the precursor of the mouth and the anterior portion of the pituitary gland. The stomodeum is ectoderm-lined depression and separates the primitive pharynx by the buccopharyngeal (oropharyngeal) membrane. The membrane later breaks down and stomodeum opens into the pharynx which then forms the vestibule of oral cavity. <ref name="PMH11936451 "><pubmed>11936451</pubmed></ref> <br />
<br />
<br />
LARYNX<br />
<br />
The larynx is developed from endoderm of laryngotracheal tube. The splanchnic mesoderm is important for the development of connective tissue and muscle as well as the laryngeal cartilages, and they develop from the 4th to the 6th pharyngeal arch mesenchyme. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref> <br />
[[File:Embryonic Trachea.png|thumb|right|550px|'''Tbx4 and Tbx5 are expressed around the condensing cartilage mesenchyme and in the intercartilage mesenchyme.''']]<br />
<br />
<br />
TRACHEA <br />
<br />
The laryngotracheal tube develops in the 4th week. The oseophagotracheal ridge separating the diverticulum forms the trachea.The epithelial cells from the foregut endoderm invade the surrounding mesenchyme to form the trachea. The trachea then divides into 2 bonchial buds, giving rise to the main bronchi, left main and right main.<ref name="PMH11992723 "><pubmed>11992723</pubmed></ref> <br />
<br />
<br />
BRONCHI<br />
<br />
The bronchi is formed in week 4 and the lung buds develop and further divide into more divisions making up 2 divisions for the left and the 3 for the right. These secondary bronchi (3 branches on the right and 2 on the left), then again divided into tertiary bronchi which occurs in week 7. The surrounding mesenchyme then develop into bronchopulmonary segments.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
BRONCHIOLES<br />
<br />
By the 24th week there would have formed approximately 17 subdivisions. After the birth of the baby the bronchiole tree further divides another 6 more divisions.<ref name="PMH12107102 "><pubmed>12107102</pubmed></ref><br />
<br />
=== Development of the Respiratory Zone===<br />
[[File:Respriatory zone.png|thumb|right|550px|'''Visualise airways.''']]<br />
The respiratory zone is where the oxygen and carbon dioxide exchange with the blood. The respiratory zone includes the terminal bronchioles, alveolar ducts and alveoli.The alveolar ducts and the bronchioles cause the 10% of gas exchange. The rest of the 90% is due to the alveoli. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
<br />
<br />
TERMINAL BRONCHIOLES<br />
<br />
Terminal bronchioles are the passageway for air to pass through from the bronchioles to the alveoli (air sacs) of the lungs.They are lined with simple columnar epithelium. This first begins to develop between week 12 and 13 of the fetus. They develop from thin squamous epithelium, and then differentiate into alveolar cells type 1 and alveolar cells type 2.<ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLAR DUCTS <br />
<br />
The alveolar ducts allows the oxygen and the carbon dioxide to move between the lungs and bloodstream. Alveolar ducts begin to develop during the late fetal period until about 8 years postnatally. They develop with extremely thin walls with many capillaries that are in close association with the alveolar epithelial cells. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref><br />
<br />
<br />
ALVEOLI<br />
<br />
The alveoli is where the carbon dioxide and the oxygen exchange. Each alveolar consists of alveolar cells; type 1 and type 2. Type 1 is a membranous pneumocyte and it serves for gas exchange, on the other hand type 2 is a granular pneumocyte that produces surfactant and it reduces surface tension and prevents the alveoli from collapsing. There would be a remodelling of the alveolar wall that results in a single capillary network, that concludes in the maturation however not a full-sized lung. <ref name="PMH8815817 "><pubmed>8815817</pubmed></ref><br />
<br />
===Lung Development Stages===<br />
<br />
{| class="wikitable"<br />
!align="center" valign="center"|Stages <br />
!align="center" valign="center"|Features<br />
|-<br />
|align="center" valign="center"|Embryonic (week 4-5)<br />
|align="center" valign="center"|Lung buds would have formed and lung lobes and the bronchopulmonary segments. The stem diverticulum will have differentiated into trachea and larynx. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Lung buds are lined by endodermally derived epithelium which differentiates into respiratory epithelium that lines the airways and specialized epithelium that lines the alveoli. [[File:Lung bud.png|thumb|right|Image of newly formed lung bud]]<br />
|-<br />
|align="center" valign="center"|Pseudoglandular (week 6-16)<br />
|align="center" valign="center"|The events that occur in this stage include the formation of extensive airway branching of about 14 or more generations of branching resulting in terminal bronchioles. Endodermal lung buds undergo branching only if they are exposed to bronchial mesoderm.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The conducting epithelium tubes are formed and are surrounded by thick mesenchyme, and the rate and extent of branching appear directly proportional to amount of mesenchyme present. At 2 months all of the segmental bronchi would have formed. The distal structures at this stage are lined with cuboidal epithelium. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Canalicular (week 16 to 25)<br />
|align="center" valign="center"|The terminal bronchioles divide into two or more respiratory bronchioles and an increase in capillaries that get in contact with the cuboidal epithelium. <ref>Cite this page: Mazurová, Y. Hrebíková, H. Embryology: Respiratory System. Retrieved 26 September, 2014, from http://web.lfhk.cuni.cz/histologie/Histols_web/Vyuka/en/tuition/general/doc/histology_II/G_II_lect_11_E_respir_syst.pdf </ref>The beginning of alveolar epithelium development is now underway and the lung morphology has drastic changes occur. the respiratory vasculature is now being developed. the differentiation of the pulmonary epithelium results in the formation of air-blood tissue barrier. This differentiation of cells transforms into specialised cell types known as ciliated, secretory,alveolar cells type 1 and 2. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref> It is notable that the differentiation of the future conducting airways of the lung from the future gas exchange region is noticeable.<ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Saccular (week 24- 40)<br />
|align="center" valign="center"|The terminal sacs along with the alveolar sacs and ducts have now formed. The saccules both widen and lengthen the air sac. There is a dramatic expansion in future gas exchange region in this stage. Fibroblasts also differentiate, they can now produce extra matrix, collagen and elastin. <ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>The vascular tree is also seen to grow in length and diameter. The terminal sacs will continue to develop until well into childhood. <ref name="PMH20692626 "><pubmed>20692626</pubmed></ref><br />
|-<br />
|align="center" valign="center"|Alveolar (week 36- 8 years of age)<br />
|align="center" valign="center"| The secondary septation occurs and a significant increase in the number and size of capillaries and alveolar.<ref>Cite this page: Rothstein, P (2014) Lung Development. Retrieved September 10, 2014, from http://www.columbia.edu/itc/hs/medical/humandev/2004/Chpt12-LungDev.pdf/ Lung Development<br />
</ref>Postnatally from 1-3 years the alveoli will continue to form and in as a result increasing the surface area for gas exchange. <ref name="PMH24058167 "><pubmed>24058167</pubmed></ref> <br />
|-<br />
|}<br />
<br />
==Understanding of Current and Direction of Future Research==<br />
<br />
<br />
Current research looks at the molecular processes that underpin two important developmental stages of the lung. The lung can anatomically be divided into two parts; an upper respiratory tract and a lower respiratory tract <ref>Cite this page: Hill, M.A. (2014) Embryology Lecture - Respiratory Development. Retrieved September 10, 2014, from https://php.med.unsw.edu.au/embryology/index.php?title=Lecture_-_Respiratory_Development</ref>. However, physiologically, the organ can be divided into two parts that occur subsequently:<br />
<br />
# The '''Conducting system'''- consisting of all the tubular structures such as the larynx, trachea, and bronchi. <br />
# The '''Functional unit'''- An alveolus. Alveoli (''Plural''). Specialised epithelial cell, the at which gas exchange of carbon dioxide and oxygen takes. <br />
<br />
Much research has been undertaken to understand how each of these processes occurs individually. However, a study conducted last year shows evidence that during later stages of fetal development, when the expands, these two important processes involve co-ordinated cellular interactions and take place at a precise time within development and at a specific location <ref name="PMID24058167"><pubmed></pubmed>24058167</ref>.<br />
<br />
By week 8, the respiratory system of the fetus is well underway and the development of the lung is at the pseudoglandular stage (see table above for more information about the properties of each stage of lung development). The three germ layers (ectoderm, mesoderm and endoderm) have each contributed to the development of the lung and their involvement is crucial for regulating a cascade of sequential of events including bronchial branching (see 1. The conducting system) and alveolar differentiation (see section 2. Functional Unit). <br />
<br />
<br />
1. '''The Conducting system''' - The respiratory network<br />
<br />
Branching morphogenesis is the growth and branching formation to build a treelike tubular network ending with specialized air bubbles (alveoli) as sites for gas exchange. <br />
<br />
• In 2013, a review study conceptualised how we now currently understand the model of branching morphogenesis. There are currently three geometrically models proposed for the way in which the primary bronchial buds branch<ref><pubmed>24004663</pubmed></ref>:<br />
<br />
:::a) Domain branching [[File:Four Models of Lung Branching.jpg|600px|thumb|Modes of branching: (a) lateral branching, (b) planar bifurcation,<br />
(c) orthogonal bifurcation and (d ) trifurcation]]<br />
:::b) Planar bifurcation<br />
:::c) Orthogonal bifurcation<br />
:::d) Trifucation <br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
<br />
• Another recent study conducted in 2013 <ref><pubmed>24058167</pubmed></ref>, suggests that there is a correlative interaction between the lung epithelium and the surrounding plural mesenchyme. The mesenchyme secretes fibroblast growth factor (FGF10) secreted by the mesenchyme, which in turn activates its membrane receptor co-worker (FGFR2). The epithelium, sequentially then generates a small amount of GTPase (KRAS). Both these contributions are involved in a cascade of signaling pathways essential for normal branching morphogenesis of the lung. <br />
<br />
[[File:Lung Fgf10 expression cartoon.jpg|centre|450px|thumb|The three types of spatial distributions of FGF10 expression generate different branching modes: (c) elongation, (d ) terminal bifurcation and (e) lateral budding. This picture depicts a model used in modern research, outlining the development of the conducting system of the lung]]<br />
<br />
<br />
• A research group in 2011 <ref><pubmed>22359491</pubmed></ref>, identified two key signalling factors; fibroblast growth factor (FGF10) and sonic hedgehog (SHH). Other signalling factors such as sonic hedgehog (SHH) receptor patched (Ptc), Bone morphogen protein (BMP4) were also identified from experiments and developed a model to explain the branching network.<br />
<br />
From their research they also conclude that the sequence of branching events may be the result of different growth speeds:<br />
::::::::::::::Faster growth factors---> triggers lateral branching<br />
::::::::::::::Slow growth factors----> bifurcated branching <br />
<br />
<br />
[[File:Signalling factors in lung branching cartoon.png|right|450px|thumb|FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression]]<br />
<br />
<br />
2. '''The Functional Unit'''-Alveolus<br />
<br />
At the end of the conducting system or at the end of the tertiary bronchial, lie the sites of gas exchange- alveolar air sacs. This process of differentiation from building on to the branched duct to specialised alveolar cells is a process named alveolar differentiation. <br />
<br />
<br />
• There are two alveolar cell types[2]:<br />
:::1. Type I alveolar cells are flat and cover more than 90% of the alveolar surface, across which gases diffuse. The exchange of carbon dioxide, CO2 for 02. However, whilst the fetus is still growing inside the uterus this gas exchange does not occur. The first breath is just after delivery and hence the first time in which the alveolar serve their purpose is after birth. <br />
<br />
:::2. Type II alveolar cells are cuboidal and play and crucial role in the respiratory development of the fetus post-natally. They synthesize pulmonary surfactants, lipoprotein complexes that hydrate the alveolar surface and prevent alveolar collapsing by reducing surface tension.<br />
<br />
==Current Models==<br />
<br />
==Animal Models==<br />
<br />
<br />
[[File:Lung Models Normal vs. Diseased.png|600px]]<br />
<br />
==Historic findings==<br />
<br />
Historical knowledge predating modern imaging techniques has most often been confirmed by contemporary studies that provided evidence for the claims of early respiratory development. At times, theories put forward for fetal respiratory development were enhanced with further detail, whereas elsewhere paradigms were shifted and challenged due to the availability of proof otherwise <ref name="PMID23431607"><pubmed>23431607</pubmed></ref>. The understanding of the development of the upper and lower respiratory system during the fetal period from week 8 onwards, as well as their respective functions, have been around since the 19th Century <ref name="PMID16601307"><pubmed>16601307</pubmed></ref>.<br />
<br />
[[File:Bailey282.jpg|center|500px]]<br />
<br />
'''Surfactant'''<br />
<br />
*1929: The earliest recorded observation regarding the necessary presence of something in the lungs was proposed by Swiss physiologist Kurt von Neergaard through experiments performed observing the surface tension within the alveoli <ref name="PMID18446178"><pubmed>18446178</pubmed></ref>. Unfortunately these findings were largely disregarded until decades later when they resurfaced in importance.<br />
<br />
*1954: Research on warfare chemicals by Pattle, Radford and Clements led to the understanding of the physical properties of surfactant <ref name="PMID15985753"><pubmed>15985753</pubmed></ref>. <br />
<br />
*1959: The final link to provide a sound understanding of the importance of surfactant was by Mary Ellen Avery and Jere Mead. They had published a study showing that premature neonates were dying from respiratory distress syndrome (RDS) due to insufficient pulmonary surfactant <ref name="PMID14509914"><pubmed>14509914</pubmed></ref>. The lung extracts obtained from hyaline membranes of babies with RDS showed this deficiency.<br />
<br />
*1963: Adams et al observed that fetal lung surfactant possessed particular characteristics that indicated it came to be present within the lung due to an active secretory process, which became foundational in linking the role of Type II pneumocytes with the secretion of surfactant. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
*1994: Discovery made regarding the reversed process of clearing pulmonary fluid from the lung rather than secreting it as surfactant by the baby upon birth, was conducted by Hummer et al. The experiment was performed in mice and indicated towards neonates who die as a result of failure to clear liquid from their lungs in the first 2 days of birth. <ref name="PMID24160653"><pubmed>24160653</pubmed></ref> <br />
<br />
[[File:Lung_historical_image.PNG|400px|thumb|Historical image of lung development]]<br />
<br />
'''Alveoli formation'''<br />
<br />
*An Italian scientist by the name of Marcello Malpighi (1628-1694) contributed greatly to medicine, particularly the understanding of anatomy as he was a pioneer biologist to utilise newly invented microscopes to closely observe. For this reason, he is most recognised as the discoverer of the pulmonary capillaries and alveoli. <ref name="PMID23377345"><pubmed>23377345</pubmed></ref><br />
<br />
*Studies of the early 1900s specifically in regards to the cellular content of alveolar wall linings indicated that there was a high presence of nucleated cells in the fetus. This led to a greater understanding in the functionality of the alveoli when just at the fetal stage. <ref name="PMID19972530"><pubmed>19972530</pubmed></ref> <br />
<br />
*J. Ernest Frazer conducted studies to research lung development along with improving the understanding of general human anatomy during his time. <ref>Keith, A. (1902) Human Embryology and Morphology. London: Edward Arnold.</ref><br />
<br />
*The differentiation of surrounding mesenchyme into alveoli was contained within a membrane known as the pleural cavity that was separated off the peritoneal and pericardial cavities --> When was this distinction discovered..<br />
<br />
<br />
1. Developmental Biology, 6th edition <br />
By <br />
Scott F Gilbert.<br />
Swarthmore College<br />
Sunderland (MA): Sinauer Associates; 2000.<br />
ISBN-10: 0-87893-243-7<br />
:'''Links:''' [http://www.ncbi.nlm.nih.gov/books/NBK9983/ | Developmental Biology]<br />
<br />
Comparative embryology with detail on historical understandings of early respiratory development observed in various species. Accessible through PubMed.<br />
<br />
2. Human Embryology and Morphology, 1902<br />
By<br />
Arthur Keith <br />
London: Edward Arnold.<br />
:'''Links:''' [http://php.med.unsw.edu.au/embryology/index.php?title=Book_-_Human_Embryology_and_Morphology_2 | Human Embryology and Morphology]<br />
<br />
Historical images of past understandings on respiratory development<br />
<br />
3. [https://m.youtube.com/watch?v=iktuxwfGpWE YouTube]<br />
Video explaining early respiratory development<br />
<br />
==Abnormalities==<br />
===Newborn Respiratory Distress Syndrome (Hyaline Membrane Disease)===<br />
Newborn Respiratory Distress Syndrome (NRDS), also known as Hyaline Membrane Disease (HMD) is characterised by the lack of or inability to synthesise surfactant in the premature lung of neonates. <br />
<br />
The incidence of NRDS occurs in babies suffering form immature lung development, usually from premature birth with increased severity and incidence in correlation to decreased gestational age <ref name="PMID20468585"><pubmed>20468585</pubmed></ref>. Preterm births do not allow for full lung maturation of the preterm infant due to process in which the respiratory system forms (from upper respiratory tree to lower). Type II Pneumocytes secrete surfactant into the alveoli, reducing surface tension and thus preventing the collapse of the alveolus – they are the last respiratory cells to differentiate. Preterm infants usually lack Type II Pneumocytes in their lung tissue causing the instability of their alveoli, oedema from immature alveolar capillaries and hyaline membrane formation<ref name="PMID6071188"><pubmed>6071188</pubmed></ref>.<br />
<br />
NRDS mostly occurs in preterm neonates but can occur in post-term and term babies for a variety of reasons including:<ref name="PMID10829971"><pubmed>10829971</pubmed></ref><br />
*Intrauterine Asphyxia – commonly caused by wrapping umbilical cord around the neck of the neonate, impairing development<ref name="PMID20468585"><pubmed>20468585</pubmed></ref><br />
*Maternal diabetes – high levels of insulin can delay surfactant synthesis<ref name="PMID20848797"><pubmed>20848797</pubmed></ref><br />
*Multiple pregnancy (twins, triplets etc) – associated with high rates of preterm births and resulting lung immaturity <ref name="PMID20848797"><pubmed>20848797<br />
</pubmed></ref><br />
*Rapid labour, fetal distress, placenta previa, preeclampsia, placental abruption – that impair lung maturation in final stages of pregnancy <ref name="PMID20848797"><pubmed>20848797</Pubmed></ref><br />
*Preterm Caesarean delivery – not allowing for lung maturation<ref name="PMID14629318"><pubmed>14629318</pubmed></ref><br />
*Genetic abnormalities that impair surfactant synthesis (ABCA3)<ref name="PMID15044640"><pubmed>15044640</pubmed></ref><br />
*Meconium Aspiration Syndrome (MAS) - causes damage to the lower respiratory tract after aspiration of Meconium in amniotic fluid<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>.<br />
<br />
===Meconium Aspiration Syndrome (MAS)===<br />
Meconium Aspiration Syndrome (MAS) affects newborn infants in response to some form of fetal stress during the third trimester and/or parturition, often due to: acute hypoxia, intrauterine hypoxia (often caused by the wrapping of the umbilical cord around the neck of the baby) and other physiological maturational events. <ref name="PMID10612363"><pubmed>10612363</pubmed></ref><ref name="PMID16651329"><pubmed>16651329</pubmed></ref>.[[File:Meconium_aspiration_syndrome_01.jpg|thumb|X-Ray showing Meconium Aspiration Syndrome in Newborn]]<br />
Stress on the baby before or during labor can cause relaxation of the anal sphincter leading to expulsion of Meconium by the foetus into the surrounding amniotic fluid which can then be aspirated by the fetus, damaging the upper respiratory tract and possibly the lower respiratory tract. <ref name="PMID19399004"><pubmed>19399004</pubmed></ref>. <br />
<br />
Problems associated with Meconium aspiration include<ref name="PMID10612363"><pubmed>10612363</pubmed></ref>:<br />
*Pulmonary gas exchange deficiency -caused by damage to the lower respiratory tract epithelium.<br />
*Pneumitis and pneumonia - due to chemical damage and irritation from Meconium interaction with the airways. <br />
*Blockage of the airways<br />
<br />
===Bronchopulmonary Dysplasia===<br />
Bronchopulmonary dysplasia (BPD) is a common complication in the treatment of Newborn Respiratory Distress Syndrome (NRDS) in infants born more than 10 weeks premature and of low weight. Efforts to treat breathing difficulties associated with NRDS can cause damage to the vulnerable lungs of the infant<ref name="PMID22785261"><pubmed>22785261</pubmed></ref>. The complications can occur from a number of reasons following treatment<ref name="PMID1971501"><pubmed>19712501</pubmed></ref>:<br />
<br />
*Oxygen therapy causing inflammation to the lung epithelium due to the higher amounts of oxygen administered<br />
*Used in more critical cases because of the complications associated with this form of treatment, air pressure from ventilation machines can further damage the premature lungs.<br />
*There is some growing evidence that genetics may play a role in the predisposition of BPD <ref name="PMID25031518"><pubmed>25031518</pubmed></ref>.<br />
*Infections from treatments involving ventilation can also occur leading to inflammation of the upper respiratory tract.<br />
<br />
<br />
===Cystic Fibrosis===<br />
Cystic fibrosis (CF) is caused by a mutations of the cystic fibrosis transmembrane conductance regulator (CFTR)<ref name="PMID24685676"><pubmed>24685676</pubmed></ref>. The defect associated with this mutation results in the excretory glands of the body producing a thick sticky mucus as well as salty sweat. The disease affects several organs in the body but mainly affects the respiratory system allowing impairing the response to bacterial infection and causing inflammation in the airways<ref name="PMID16928707"><pubmed>16928707</pubmed></ref><ref name="PMID22763554"><pubmed>22763554</pubmed></ref>. This aberrant production of mucus can lead to the mucus stasis in the pulmonary epithelium, airway plugging, inflammation and chronic bacterial infection causing the decrease in lung function. <br />
<br />
===Laryngeal Atresia===<br />
Laryngeal Atresia (LA) is incredibly rare and occurs as a failure of the laryngo-tracheal tube to recanalise, obstructing the upper respiratory tract leading to a larynx with no lumen<ref name="PMID14325849"><pubmed>14325849</pubmed></ref>. This can cause Congenital High Airway Obstruction Syndrome (CHAOS) <ref name="PMID2342705"><pubmed>2342705</pubmed></ref>. Genetic abnormalities have been identified as having an association with AL <ref name="PMID3566610"><pubmed>3566610</pubmed></ref>.<br />
<br />
===Congenital High Airway Obstruction Syndrome (CHAOS)===<br />
Congenital High Airway Obstruction Syndrome (CHAOS) is extremely rare and is the result of an obstruction to the fetal airways. This obstruction can be caused by atresia of the larynx or trachea, laryngeal cysts, laryngeal webs and subglottic stenosis<ref name="PMID22167132"><pubmed>22167132</pubmed></ref>. Reviews have revealed that most cases are fatal<ref name="PMID12778398"><pubmed>12778398</pubmed></ref> but ex-utero partum treatments (EXIT) have been successful in treating this condition<ref name="PMID9802816"><pubmed>9802816</pubmed></ref><br />
<br />
===Congenital Laryngeal Webs===<br />
Similarly to Laryngeal Atresia, Congenial Laryngeal Webs (CLW) are caused by failure of the laryngo-tracheal tube to recanalise, usually at the level of the vocal chords. The lumen and vocal chords of the larynx is usually developed after the epithelium is reabsorbed but in the case of CLW, this reabsorption is incomplete leaving ‘web-like’ formations in the larynx that obstruct normal development and airflow. <ref name="PMID16798587"><pubmed>16798587</pubmed></ref><br />
<br />
===Congenital Pulmonary Airway Malformation===<br />
Congenital Pulmonary Airway Malformation (CPAM) occurs at varying degrees and is defined by its location in and the level of differentiation of alveoli<ref name="PMID24672262"><pubmed>24672262</pubmed></ref>. In the cases of type I and II, CPAM involves the presence of cysts affecting the terminal bronchioles and lung parenchyma. CPAM is thought to be caused by an abnormal development of the lung bud in week 4-5 of development and leads to the malformation of the pulmonary airways via the formation of lung abscesses, pulmonary infections and the sequestration of areas of the lung<ref name="PMID21355683"><pubmed>21355683</pubmed></ref>. Recent reviews have also suggest that thyroid transcription factor 1 (TTF1) may have a role in CPAM as it is involved in the differentiation of lung epithelium and overall pulmonary development. <ref name="PMID21762550"><pubmed>21762550</pubmed></ref>.<br />
<br />
*Type I - is defined by large multilocular cysts occurring in one of the pulmonary lobes<br />
*Type II – define by the presence of smaller more uniform cysts.<br />
*Type III – is defined by larger lesions that affect the lung parenchyma of en entire lobe.<br />
<br />
===Azygos Lobe===<br />
Azygos lobe (also known as Adam's lobe) occurs due to the aberrant formation of the azygos vein as it veers from its normal course over the apex of the right lung to penetrate the upper lobe. An accessory fissure is formed in the upper lobe and the pulmonary parenchyma located in the medial portion is identified as the Azygos Lobe. There have been three observed types of azygos lobe that are relatively harmless and present little clinical significance (except during surgery due to variations in the course of the phrenic nerve): <ref name="PMID16333920"><pubmed>16333920</pubmed></ref>.<br />
*Upper Azygos Lobe <br />
*Lower Azygos Lobe <br />
*the Lobe of the Azygos Vein <br />
<br />
===References===<br />
<references/><br />
<br />
<br />
==Glossary==<br />
'''occlusion'''Blockage or obstruction of a vessel</div>
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File:Signalling factors in lung branching cartoon.png
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<p>Z3332339: /* Signalling factors in lung branching cartoon */</p>
<hr />
<div>==Signalling factors in lung branching cartoon==<br />
<br />
A graphical summary of the modelled interactions of the signaling factors in lung bud during morphogenesis.<br />
<br />
GF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression.<br />
<br />
===Reference===<br />
<br />
Menshykau D, Kraemer C, Iber D (2012) Branch Mode Selection during Early Lung Development. PLoS Comput Biol 8(2): e1002377. doi:10.1371/journal.pcbi.1002377<br />
<br />
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002377<br />
<br />
<br />
===Copyright Information===<br />
<br />
© 2012 Menshykau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
<br />
<br />
{{Template:Student Image}}</div>
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https://embryology.med.unsw.edu.au/embryology/index.php?title=File:Signalling_factors_in_lung_branching_cartoon.png&diff=157838
File:Signalling factors in lung branching cartoon.png
2014-10-23T15:30:06Z
<p>Z3332339: ==Signalling factors in lung branching cartoon==
A graphical summary of the modelled interactions of the signaling factors in lung bud during morphogenesis.
FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest...</p>
<hr />
<div>==Signalling factors in lung branching cartoon==<br />
<br />
A graphical summary of the modelled interactions of the signaling factors in lung bud during morphogenesis.<br />
<br />
FGF10 is transcribed at high levels in the distal mesenchyme (grey) and experiments suggest that FGF10 promotes both the proliferation of the endoderm and its outward movement (green arrow). FGF10 stimulates the expression of SHH in the epithelium (red). SHH reversibly binds its receptor Ptc1 which is expressed in the mesenchyme (grey). SHH-Ptc binding results in the repression of FGF10 expression.<br />
<br />
===Reference===<br />
<br />
Menshykau D, Kraemer C, Iber D (2012) Branch Mode Selection during Early Lung Development. PLoS Comput Biol 8(2): e1002377. doi:10.1371/journal.pcbi.1002377<br />
<br />
http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1002377<br />
<br />
<br />
===Copyright Information===<br />
<br />
© 2012 Menshykau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.<br />
<br />
<br />
{{Template:Student Image}}</div>
Z3332339